JP6391076B2 - Androgen receptor modulators and uses thereof - Google Patents

Description

  This application claims the benefit of U.S. Provisional Patent Application No. 61 / 231,660, filed February 16, 2010, entitled "ANDROGEN RECEPTOR MODULATORS AND USES THEREOF", filed April 28, 2010. US Provisional Patent Application No. 61 / 329,023 entitled ANDROGEN RECEPTOR MODULATORS AND USES THEREOF and US Provisional Patent Application entitled ANDROGEN RECEPTOR MODULATORS AND USES THEREOF filed on September 30, 2010 No. 61 / 388,457 claims the benefit of which is incorporated herein by reference in its entirety.

  Pharmaceutically acceptable salts, solvates, metabolites, compounds including prodrugs, methods of producing such compounds, pharmaceutical compositions comprising such compounds, androgen receptor dependent, or androgen Described herein are methods of using such compounds to treat, prevent or diagnose receptor-mediated diseases or disorders.

  The androgen receptor ("AR") is a ligand-activated transcription regulatory protein that mediates the induction of various biological actions through interactions with endogenous androgen is there. Endogenous androgens include steroids such as testosterone and dihydrotestosterone. Testosterone is converted to dihydrotestosterone by the enzyme 5-alpha reductase in many tissues.

  The action of androgen on the androgen receptor has been linked to a number of diseases or diseases, in particular androgen-dependent cancer, maleification in women and acne. Compounds that attenuate the action of androgen by androgen receptors and / or reduce the concentration of androgen receptors are found for use in the treatment of diseases or conditions where the androgen receptor plays a major role.

  In one embodiment, a disease or disorder that attenuates the action of androgen by the androgen receptor and / or reduces the concentration of the androgen receptor, and thus the androgen receptor plays a major role, such as a disease of the androgen receptor And / or a pharmaceutically useful compound for treating or preventing a disease or disorder that is involved in, related to, or contributes to at least one symptom of the disease or disorder I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or ( Compounds of X) are presented herein.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compound of (IXa) or (X) may be benign prostate hypertrophy, hirsutism, acne, adenoma and proplasies of the prostate, benign or malignant tumor cells including androgen receptor, ultra-rich hair, Seborrhoea, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppression of spermatogenesis, sexual desire, cachexia, loss of appetite, decrease in age-related testosterone levels Androgen replacement, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flush, and Kenedy's muscle atrophy and weakness, skin atrophy, bone loss, anemia, arteriosclerosis, cardiovascular disease, activity Loss of, loss of health, type 2 diabetes, and is useful for the accumulation of abdominal fat. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are used in the treatment of prostate cancer. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are used in the treatment of hormone-sensitive prostate cancer. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are used in the treatment of hormone refractory prostate cancer.

  In one aspect, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), Compounds of (IXa), or (X), pharmaceutically acceptable salts, solvates, metabolites, and prodrugs thereof are described herein. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are androgen receptor modulators. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) is an androgen receptor antagonist, an androgen receptor inverse agonist, an androgen receptor degrader, an androgen receptor transport modulator, and / or androgen receptor DNA binding It is an inhibitor. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are androgen receptor antagonists. In some embodiments, of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) The compounds are androgen receptor inverse agonists. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are androgen receptor degraders. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa), or (X) are androgen receptor transport modulators. In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) are inhibitors of androgen receptor DNA binding.

  In one aspect, provided herein is a compound of formula (I), a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof,

here,
Ring A is monocyclic heteroaryl, bicyclic heteroaryl or naphthyl, and
m is 0, 1, 2, 3 or 4;
Each R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl substituted, substituted or unsubstituted phenyl, there have Are independently selected from monocyclic heteroaryl, substituted or unsubstituted,
Each R ¹ is selected from H, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl Independently selected,
Alternatively, both R ¹ may be substituted with the carbon atom to which R ¹ is attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl. Taken together,
Each R ² is H, or both R ² are taken together with the carbon to which they are attached to form —C (= S) — or —C (= O) — ,
Each R ³ is H or both R ³ are taken together with the carbon to which they are attached to form —C (= S) — or —C (= O) — If each R ³ is H then each R ² is not H,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1, 2, 3 or 4;
Each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-OCO 2 R 10, -N (R}} 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N ( R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoro Alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ independently selected from heteroalkyl,
R ⁵ is substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkoxy, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₂ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterofluoroalkyl, or -L ¹ -L ² -R ⁶ and L ¹ is absent Or -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O-, -OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene,
R ⁶ represents a halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} hetero Black alkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl,
Each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or non Substituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl) And -C ₁ -C ₄ alkylene- (substituted (or unsubstituted heteroaryl) independently selected from
Alternatively, two R ⁹ groups attached to the same N atom are taken together with the N atom attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- ( substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted Substituted aryl) or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

For any and all embodiments, substituents are selected from among the listed subsets of alternatives. For example, in some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R ¹ is independently selected from H, -OH, C ₁ -C ₆ alkyl, and C ₁ -C ₆ fluoroalkyl, respectively. In some embodiments, each R ⁵ is independently selected from H, -CH ₃ , and -CF ₃ .

In some embodiments, both R ² are taken together with the carbon to which they are attached to form —C (= S) —, and both R ³ are —C (= O) — Are taken together with the carbon to which they are attached.

  In some embodiments, ring A is a C-linked monocyclic heteroaryl, a C-linked bicyclic heteroaryl or naphthyl.

In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, and both R ² are They are incorporated together with the carbon to which they are attached to form C (= S)-, and both R ³ are together with the carbon to which they are attached to form -C (= O)- Embedded, ring A is N-containing monocyclic heteroaryl or N-containing bicyclic heteroaryl, and each R ^A is H, halogen, -CN, -NO ₂ , -OH _{^{, -S (= O) 2 R}} 10, -N (R 11) S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, - _{^{OC (= O) R 10,}} -CO 2 R 9, -C (= O) N (R 9) 2, substituted or unsubstituted Substituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or non It is independently selected from substituted phenyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and ring A is pyridinyl, pyrimidinyl, pyridazinyl And N which is a monocyclic heteroaryl selected from pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl.

  In some embodiments, ring A is pyridinyl, pyrimidinyl or pyridazinyl. In some embodiments, ring A is pyridinyl.

  In some embodiments,

Is

It is. In some embodiments,

Is

It is.

In some embodiments, ring A is pyridinyl and each R ^A is H, halogen, —CN, —OH, —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _1- It is independently selected from C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and ring A is quinolinyl, isoquinolinyl, quinazolinyl , Quinoxalinyl, naphthyridinyl (naphthyridinyl), indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl (purinyl), cinazolyl, phthalazinyl, pteridinyl, pyridopyrimidinyl (pyridopyrimidinyl), Pyrimidololy (pyrazolopyrimidinyl), azaindolyl (azaindolyl), pyrazolo pyridin Nil (pyrazolopyridinyl), thiazolopyrimidinyl (thiazolopyrimidinyl), triazolopyridazinyl (triazolopyridazinyl), thiazolo pyridinyl (thiazolopyridinyl), pyridothienyl, pyrimidiothienyl, pyri ) a bicyclic heteroaryl containing selected N- from, each of ^{R a,} H, ^{_{halogen, -CN, -OH, -S (=}} O) 2 R 10, -S (= O) _{^{2 N (R 9) 2,}} -C (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ Furuoroa Kill, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted phenyl, or, independently of the monocyclic heteroaryl, substituted or unsubstituted It is selected.

  In some embodiments, ring A is an N-containing bicyclic selected from quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, triazolopyridazinyl, and pyrrolopyrimidinyl. It is heteroaryl.

  In some embodiments, ring A is [1,2,4] triazolo [4,3-b] pyridazinyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl and each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ R ⁵ is independently selected from —C ₆ heteroalkyl and R ⁵ is substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkoxy, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₂ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterof Fluoroalkyl, or ^{a -L 1 -L 2 -R 6, L} 1 is absent, -O -, - S -, - S (= O) -, - S (= O) 2 -, - NH -, - C (= O ) -, - C (= O) NH -, - NHC (= O) -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH- , L ² is substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or substituted or unsubstituted C ₁ -C ₆ heteroalkylene, and R ⁶ is , _{^{halogen, -CN, -NO 2, -OH,}} -OR 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) 2 N (R _{^{9) 2, -C (= O}} ) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) N (R 9) 2, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted It is phenyl or substituted or unsubstituted naphthyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl, and each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₄ R ⁵ independently selected from alkyl, substituted or unsubstituted C ₁ -C ₄ fluoroalkyl, substituted or unsubstituted C ₁ -C ₄ fluoroalkoxy, and substituted or unsubstituted C ₁ -C ₄ alkoxy; Is substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkoxy, substituted or unsubstituted C ₂ -C ₁₀ fluoro alkoxy, substituted or unsubstituted _C 2 _{-C 10} heteroalkyl, substituted or unsubstituted _C 2 _{-C 10} heteroalkyl fluoroalkyl ^{or,, -L} 1 -L 2 -R ⁶ There, ^{L 1} is absent, -O or,, -C (= O) a NH-, ^{L 2} is a substituted or unsubstituted _C 1 -C ₆ alkylene, substituted or unsubstituted _{C 1} - C ₆ fluoroalkylene or substituted or unsubstituted C ₁ -C ₆ heteroalkylene, wherein R ⁶ is -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -C (= O) R ¹⁰ , -CO ₂ R ⁹ , -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or substituted Or unsubstituted naphthyl.

In some embodiments, L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, and R ⁶ is -CN, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ ,- _{^{S (= O) 2 R 10}} , -C (= O) R 10, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl.

In some embodiments, R ⁶ is substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted Or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted naphthyl.

In some embodiments, L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, and R ⁶ is -CN, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ ,- S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ or —C (= O) N (R ⁹ ) ₂ , and each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - ( Substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl) Selected from) or the same N atom The two R ⁹ groups attached, to form a C ₂ -C ₁₀ heterocycloalkyl substituted or unsubstituted, it is taken together with the N atom to which attached, R ¹⁰ is a substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene -(Substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (substituted or unsubstituted Heteroaryl).

  In some embodiments, provided is a compound of Formula (Ia), a pharmaceutically acceptable salt or N-oxide thereof:

here,
Ring A is monocyclic heteroaryl, bicyclic heteroaryl or naphthyl, and
m is 1, 2, 3 or 4 and each R ^A is independently H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S ( _{^{= O) R 10, -S (}} = O) 2 R 10, -N (R 11) S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O ) R ¹⁰ , -OC (= O) R ¹⁰ , -CO ₂ R ⁹ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C _1- C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy or C ₁ -C ₆ heteroalkyl;
Both R ¹ are taken together with the carbon to which they are attached to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl. ,
Alternatively, each R ¹ is independently selected from H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ fluoroalkyl;
X is S or O,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1, 2, 3 or 4;
Each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-OCO 2 R 10, -N (R}} 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N ( R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, Independently selected from C ₁ -C ₆ alkoxy and C ₁ -C ₆ heteroalkyl;
R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ,
L ¹ is absent, -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) ) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (-) = O) O -, - OC (= O) NH-, NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene,
R ⁶ represents a halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl Substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl,
R ⁷ is a substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl or a substituted or unsubstituted monocyclic heteroaryl;
Each R ⁹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 -C ₆ cycloalkyl), - C ₁ -C ₄ alkylene- (substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted phenyl), and -C ₁ -C ₄ independently selected from ₄ alkylene- (substituted or unsubstituted monocyclic heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl.
R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl, _-C 1 -C ₄ alkylene - (substituted and unsubstituted _C 3 -C ₆ cycloalkyl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted phenyl), or And -C ₁ -C ₄ alkylene- (substituted or unsubstituted monocyclic heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl, X is S and the ring A is a monocyclic heteroaryl containing N, and each R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -N (R ^{11 _{) S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -C (= O) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, and independently selected from C ₁ -C ₆ alkoxy, the ring B is phenyl or monocyclic heteroaryl.

In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and ring A is pyridinyl, pyrimidinyl, pyridazinyl Or pyrazinyl.

In some embodiments, ring A is pyridinyl and each R ^A is H, halogen, —CN, —OH, —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, and independently from C ₁ -C ₆ alkoxy To be selected.

In some embodiments, ring B is phenyl, R ⁵ is -L ¹ -L ² -R ⁶ and L ¹ is absent, -O-, -S-, -S (= O )-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHS (= O) _2- , Or -S (= O) ₂ NH-, L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene, or C ₁ -C ₆ heteroalkylene, R ⁶ is a halogen, _{^{-CN, -NO 2, -OH, -OR}} 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) 2 N (R 9) 2 _{^{, -C (= O) R 10}} , -CO 2 R 9, -N (R 9) 2, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 -C ₆ cycloalkyl , Substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or a substituted or unsubstituted phenyl.

In some embodiments, ring B is phenyl and each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, and independently selected from C ₁ -C ₄ alkoxy, R ⁵ is -L ¹ -L ² -R ⁶ and L ¹ is absent, -O-, or , -C (= O) NH-, L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene, R ⁶ is -CN, _{^{-NO 2, -OH, -OR 9,}} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -C (= O) R 10, -CO 2 R 9, - C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₆ cycloalkyl Or substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, L ² is C ₁ -C ₆ alkylene and R ⁶ is —CN, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocyclo It is alkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted phenyl.

In some embodiments, R ⁶ is substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or , Substituted or unsubstituted phenyl.

In some embodiments, L ² is C ₁ -C ₆ alkylene and R ⁶ is a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl.

In some embodiments, ring B is phenyl and each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, and independently selected from C ₁ -C ₄ alkoxy, R ⁵ is -L ¹ -R ⁷ and L ¹ is absent or -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O-, -OC (= O) NH-,- NHS (= _{O) 2} -, or, -S _{(= O)} a 2 NH-, ^{R 7} is a substituted or unsubstituted monocyclic _C 2 -C ₆ heterocycloalkyl, there Is a monocyclic heteroaryl, substituted or unsubstituted.

In some embodiments, R ⁵ is -L ¹ -R ⁷ and L ¹ is -O-, -S-, -S (= O)-, -S (= O) _2- , -NH -, -C (= O)-, -C (= O) NH- or -S (= O) ₂ NH-, and R ⁷ is a substituted or unsubstituted monocyclic C ₂ -C ₆ Heterocycloalkyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R ⁵ is -L ¹ -R ⁷ and L ¹ is absent, -O-, -S-, -S (= O)-, -S (= O) ₂ —, —NH—, —C (= O) —, —C (= O) NH— or —S ((O) ₂ NH—, wherein R ⁷ is a substituted or unsubstituted monocyclic heteroaryl It is.

  In some embodiments, the compound of Formula (I) or Formula (Ia) has the structure of Formula (II).

  In some embodiments, the compound of Formula (Ia) has the structure of Formula (II):

here,

Is

And
m is 2 and
One R ^A is —CN, —NO ₂ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ or -C (= O) N (R ⁹ ) ₂ , and another R ^A is H, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy,
n is 0 or 1 and
Each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, and C ₁ -C ₆ Independently selected from alkoxy
R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ,
L ¹ is absent, -O-, or -C (= O) NH-,
L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene,
R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , _{^{-CO 2 R 9, -N (R}} 9) 2, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 -C ₆ cycloalkyl, substituted or unsubstituted _C 2 -C ₆ Heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted phenyl,
R ⁷ is a substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl or a substituted or unsubstituted monocyclic heteroaryl.

  In some embodiments,

Is

And
One R ^A is -CN and the other R ^A is H, halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy or C an ₁ -C ₄ alkoxy, each ^{R 4} is, H, halogen, _-OH, C 1 -C _{4 alkyl,} C 1 -C _{4 fluoroalkyl,} C 1 -C ₄ fluoroalkoxy, _and, C 1 -C R ⁵ is independently selected from ₄ alkoxy, R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ , L ¹ is absent, -O-, or -C (= O A) NH-, L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene, and R ⁶ is —CN, —NO ₂ , —OH , -OR ⁹ , -SR ⁹ , -S (= O) R _{^{10, -S (= O) 2}} R 10, -C (= O) R 10, -CO 2 R 9, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 -C ₆ Cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted phenyl, and R ⁷ is a substituted or unsubstituted single ring formula C ₂ -C ₆ heterocycloalkyl, or a monocyclic heteroaryl, substituted or unsubstituted.

  In one embodiment, a compound of formula (I), a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof is described herein:

here,
Ring A is bicyclic heteroaryl or naphthyl,
m is 0, 1, 2 or 3
Each R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl substituted, substituted or unsubstituted phenyl, there have Are independently selected from monocyclic heteroaryl, substituted or unsubstituted,
Each R ¹ is selected from H, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl Independently selected,
Alternatively, both R ¹ together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl Into the
Each R ² is H, or both R ² are taken together with the carbon to which they are attached to form —C (= S) — or —C (= O) —
Each R ³ is H, or both R ³ are taken together with the carbon to which they are attached to form —C (= S) — or —C (= O) — If each R ³ is H then each R ² is not H,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2 and
Each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-OCO 2 R 10, -N (R}} 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N ( R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoro Alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ independently selected from heteroalkyl,
R ⁵ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ^{11) _{) S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , -OC (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) N (R ⁹ ) ₂ ) —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted _C 1 _{-C 10 fluoroalkoxy,} C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 _{-C 10} heteroalkyl ^{Alternatively,} a ^-L 1 -L 2 -R ^6,
L ¹ is absent, -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) ) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (-) = O) O -, - OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene,
R ⁶ represents a halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} hetero Black alkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl,
Each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or non Substituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl) And -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments, ring A is quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, purinyl, cinnorinyl, phthalazinyl Selected from pyridopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, pyrazolopyridinyl, thiazolopyrimidinyl, triazolopyridazinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyl, pyrrolopyrimidinyl, and naphthyl Ru.

  In some embodiments, ring A is selected from quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, triazolopyridazinyl, pyrrolopyrimidinyl, and naphthyl.

  In some embodiments, ring A is [1,2,4] triazolo [4,3-b] pyridazinyl.

  In one embodiment, a compound of formula (I), a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof is described herein:

here,
Ring A is a 5-membered heteroaryl,
m is 0, 1, 2, or 3;
Each R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₄ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl substituted, substituted or unsubstituted phenyl, there have Are independently selected from monocyclic heteroaryl, substituted or unsubstituted,
Each R ¹ is selected from H, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl Independently selected,
Alternatively, both R ¹ together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl Into the
Each R ² is H, or both R ² are taken together with the carbon to which they are attached to form —C (= S) — or —C (= O) —
Each R ³ is H, or both R ³ are taken together with the carbon to which they are attached to form —C (= S) — or —C (= O) — If each R ³ is H then each R ² is not H,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
Each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-OCO 2 R 10, -N (R}} 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N ( R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoro Alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ independently selected from heteroalkyl,
R ⁵ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ^{11) _{) S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , -OC (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) N (R ⁹ ) ₂ ) —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted _C 1 _{-C 10} fluoroalkoxy, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 -C ₀ heteroalkyl, or ^{a -L} 1 -L 2 -R ^6,
L ¹ is absent, -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) ) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (-) = O) O -, - OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene,
R ⁶ represents a halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} hetero Black alkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl,
Each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or non Substituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl) And -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments, ring A is selected from pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl, and tetrazolyl.

  In some embodiments,

Is

Is selected from X is O, S or NR ^A. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR ^A.

In some embodiments, both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₁₀ cycloalkyl, and both R ² are —C (= S) - in order to form a, taken together with the carbon to which they are attached, both of R ³ are, -C (= O) - in order to form a, it incorporated together with the carbon to which they are attached.

  In some embodiments, the compounds described herein have the structure of Formula (III):

Here, p is 0, 1, 2 or 3.

In some embodiments, each R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) _{2 ^{, -C (= O) R 10}} , -CO 2 R 9, -C (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C Independently from ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl To be selected.

In some embodiments, each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoro R ⁵ is independently selected from alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, and substituted or unsubstituted C ₁ -C ₆ alkoxy, and R ⁵ is substituted or unsubstituted C ₂ -C ₁₀ alkyl , Substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkoxy, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₂ -C ₁₀ hetero Alkyl, substituted or unsubstituted C ₂ -C ₁₀ heterofluoroalkyl, or -L ¹ -L ² -R ⁶ , wherein L ¹ is absent, -O-, -S-,- S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHS (= O) And ₂ )-or -S (= O) ₂ NH-, wherein L ² is substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or substituted Or unsubstituted C ₁ -C ₆ heteroalkylene, wherein R ⁶ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S ( = O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -CO ₂ R ⁹ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or Is unsubstituted monocyclic heteroalkyl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted naphthyl.

In some embodiments, each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoro R ⁵ is independently selected from alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, and substituted or unsubstituted C ₁ -C ₆ alkoxy, and R ⁵ is H, halogen, -CN, -NO ₂ , _{^{-OH, -OR 9, -SR 9,}} -S (= O) R 10, -S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R ¹⁰ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted _C 1 _{-C 10} fluoroalkyl, substituted or Is unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ heteroalkyl, or -L ¹ -L ² -R ⁶ , L ¹ is absent, -O-, or -C (= O) NH-, and L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C _1- C ₆ heteroalkylene, R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ hetero Cycloalkyl, substituted or unsubstituted monocyclic heteroaryl, Or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl.

  In some embodiments, a compound of Formula (IV), a pharmaceutically acceptable salt, solvate, N-oxide, metabolite, or prodrug thereof is described herein:

here,
Each R ¹ is selected from H, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl Independently selected,
Alternatively, both R ¹ together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl Into the
X ¹ is CR ^A or N,
X ² is CR ^A or N,
X ³ is CR ^A or N, and at least two of X ¹ , X ² and X ³ are CR ^A ,
Each R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl substituted, substituted or unsubstituted phenyl, there have Are independently selected from monocyclic heteroaryl, substituted or unsubstituted,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted Substituted C ₁ -C ₆ heteroalkyl,
R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, -NR 11 C (= O) R 10, - NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 _{-C 10} heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl conversion, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or,, ^-L 1 -L ² -R ⁶ and
L ¹ is absent, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH -, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) ) O -, - OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene,
R ⁶ is -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ¹⁰ , -CO ₂ R ⁹ , -OCO ₂ R ¹⁰ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, - NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted Unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl,
Each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - Independently selected from (substituted or unsubstituted aryl) and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
Each R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - (substituted Or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments,

Is

And
m is 0, 1, 2, 3 or 4.

  In some embodiments,

Is

It is.

  In some embodiments, the compound of Formula (IV) has a structure of Formula (V).

In some embodiments, ring B is phenyl and R ⁴ is H, halogen, -CN, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ Fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, or substituted or unsubstituted C ₁ -C ₆ alkoxy, and R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR _{^{9, -SR 9, -S (=}} O) R 10, -S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -CO ₂ R ⁹ , -N (R ⁹ ) ₂ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, _C 1 _{-C 10} al of substituted or unsubstituted Alkoxy, substituted or unsubstituted _C 1 _{-C 10} heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted phenyl, substituted Or unsubstituted monocyclic heteroaryl or -L ¹ -L ² -R ⁶ , wherein L ¹ is absent, or -O-, -S-, -S (O)-, -S ( O) _2- , -NH-, -C (= O)-, -C (= O) NH- or -S (= O) ₂ NH-, and L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted _C 1 -C ₆ fluoroalkylene, or a _C 1 -C ₆ heteroalkylene substituted or unsubstituted, ^{R 6} is, _-CN, -NO 2, -OH, ^{-OR 9, -SR 9, -S (} = O) R 10, -S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -CO 2 R 9, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl .

In some embodiments, each R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) _{2 ^{, -C (= O) R 10}} , -CO 2 R 9, -C (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C It is independently selected from ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, or substituted or unsubstituted C ₁ -C ₆ alkoxy.

  In some embodiments, a compound of Formula (I) (Ia) (II), (IV), or (V) has a structure of Formula (VI).

  In some embodiments, the compound of Formula (I) (Ia) (II), (IV), or (V) has the structure of Formula (VI):

here,
One R ^A is —CN, —NO ₂ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ or -C (= O) N (R ⁹ ) ₂ , and another R ^A is H, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy,
Both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl.
Alternatively, each R ¹ is independently C ₁ -C ₄ alkyl,
R ⁴ is H, halogen, -OH, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy or C ₁ -C ₄ alkoxy.

In some embodiments, R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ and L ¹ is absent, -O-, or -C (= O) NH-, L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene, and R ⁶ is —CN, —NO ₂ , — _{^{OH, -OR 9, -SR 9,}} -S (= O) R 10, -S (= O) 2 R 10, -C (= O) R 10, -CO 2 R 9, -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted phenyl substituted, ^{R 7} is a substituted or unsubstituted monocyclic _C 2 -C ₆ Heteroshi Roarukiru, or a monocyclic heteroaryl, substituted or unsubstituted.

In some embodiments, one R ^A is —CN, —NO ₂ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl, and one more R ^A is H, halogen, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, or Substituted or unsubstituted C ₁ -C ₆ alkoxy, R ⁴ is H, halogen, -CN, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ Fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ Ruoroarukokishi, or a substituted or unsubstituted _C 1 -C ₆ alkoxy, ^{R 5} is ^{_{halogen, -CN, -NO 2, -OH,}} -OR 9, -S (= O) 2 R 10, _{^{-S (= O) 2 N (}} R 9) 2, -C (= O) R 10, -CO 2 R 9, substituted or unsubstituted _C 2 _{-C 10} alkyl, substituted or unsubstituted _C 2 -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, ^{or,, -L} 1 -L 2 -R ⁶ There, ^{L 1} is absent, -O-, or, -C (= O) a NH-, ^{L 2} is a substituted or unsubstituted _C 1 -C ₆ alkylene, substituted or unsubstituted _{C 1} -C ₆ fluoroalkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene, wherein R ⁶ is -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O ) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , substituted or non- It is substituted monocyclic heteroaryl or substituted or unsubstituted phenyl.

  In one embodiment, a compound of formula (VII), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof is described herein:

here,
Each R ¹ is selected from H, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl Independently selected,
Alternatively, both R ¹ together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl Into the
Each R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ^{9 _{-N (R 9) 2, -C}} (= O) N (R 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl , Substituted or unsubstituted phenyl, or substituted or unsubstituted hetero Independently selected from the reel,
Ring B is a 5-membered heteroaryl, bicyclic heteroaryl or naphthyl,
n is 0, 1 or 2;
R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, or substituted or unsubstituted C ₁ -C ₆ alkoxy,
R ⁵ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ^{11) _{) S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , -OC (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) N (R ⁹ ) ₂ ) —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted _C 1 _{-C 10} fluoroalkoxy, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 -C ₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or, , -L ¹ -L ² -R ⁶ ,
L ¹ is absent, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH -, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) ) O -, - OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene,
R ⁶ represents a halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (OO) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, Substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl Ri,
Each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - Independently selected from (substituted or unsubstituted aryl) and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- ( substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted Substituted aryl) or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In one embodiment, a compound of formula (VIII), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof is described herein:

here,
Each R ¹ is selected from H, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl Independently selected,
Alternatively, both R ¹ together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl Into the
X is O or S,
Each R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N ( R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, C 1 -C 6 _alkyl, C 1 -C _{6 alkoxy,} C 1 -C ₆ heteroalkyl, substituted or unsubstituted _{C 3} -C ₁₀ cycloalkyl, independently selected from substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, or substituted or unsubstituted Substituted C ₁ -C ₆ heteroalkyl,
R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (OO) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted _C 1 _{-C 10} fluoroalkoxy unsubstituted, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 _{-C 10} of Heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or, -L ¹ -L ² -R ⁶ ,
L ¹ is absent, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH -, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) ) O -, - OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene,
R ⁶ is -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ¹⁰ , -CO ₂ R ⁹ , -OCO ₂ R ¹⁰ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, - NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted Unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl,
Each R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - Independently selected from (substituted or unsubstituted aryl) and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- ( substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted Substituted aryl) or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

In some embodiments, X is S, ring B is phenyl and R ⁴ is H, halogen, -CN, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy, wherein R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , _{^{-S (= O) 2 R 10}} , -S (= O) 2 N (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C ( = O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _{C 1} - ₁₀ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or, , -L ¹ -L ² -R ⁶ , L ¹ is absent, or -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O) —, —C (= O) NH— or —S (= O) ₂ NH—, wherein L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or substituted or unsubstituted C ₁ -C ₆ heteroalkylene, wherein R ⁶ is -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S ( _{^{= O) R 10, -S (}} = O) 2 R 10, -S (= O _{^{2 N (R 9) 2,}} -CO 2 R 9, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} of Heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl.

In some embodiments, each R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ And —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy, independently selected from Ru.

  In some embodiments, a compound of Formula (VIIIa), or a pharmaceutically acceptable salt, solvate, or N-oxide thereof is described herein:

here,
Both R ¹ are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or alternatively a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl ,
Or
Each R ¹ is independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ fluoroalkyl,
X is O or S,
R ^A is C ₁ -C ₆ alkyl,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , C ₁ -C ₆ Alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy or C ₁ -C ₆ heteroalkyl;
R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9) 2}} , -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2 , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C _{10 alkoxy,} C 1 _{-C 10} heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _{C 2} - ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or ^{a -L} 1 -L 2 -R ^6,
L ¹ is absent, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH -, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) ) O -, - OC (= O) NH -, - NHS (= O) 2 -, or, -S _{(= O)} is 2 NH-,
L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene,
R ⁶ is -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ¹⁰ , -CO ₂ R ⁹ , -OCO ₂ R ¹⁰ , _{^{-N (R 9) 2, -C}} (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, - NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted Unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl,
Each R ⁹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl Alkyl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene-(substituted or unsubstituted aryl), and -C _1- Independently selected from C ₄ alkylene- (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl),- C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (Substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

In some embodiments, X is S, ring B is phenyl and R ⁴ is H, halogen, -CN, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy, wherein R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , _{^{-S (= O) 2 R 10}} , -S (= O) 2 N (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C ( = O) N (R ⁹ ) ₂ , C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ heteroalkyl, substituted or Unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or ^{a -L} 1 -L 2 -R ^6, or ^{L 1} is absent, -O -, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH- or -S (= O) ₂ NH-, L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene, and R ⁶ is -CN, -NO ₂ , -OH , -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -CO ₂ R ⁹ , -C ^{(= O) N (R 9} ) 2, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 -C ₁ Heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, or a substituted or unsubstituted aryl.

In some embodiments, R ^A is C ₁ -C ₆ alkyl, and both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl. Alternatively, each R ¹ is independently C ₁ -C ₄ alkyl.

  In some embodiments, the compound of Formula (VIII) has a structure of Formula (IX).

In some embodiments, each R ^A is independently selected from H, halogen, -OH, C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkoxy.

  In some embodiments, the compound of Formula (VIII) or Formula (VIIIa) has the structure of Formula (IXa).

In some embodiments, each R ⁹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl , Independently selected from substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl and substituted or unsubstituted monocyclic heteroaryl, or Two R ⁹ groups attached to the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, R ¹⁰ is C ₁ -C _{6 alkyl,} C 1 -C _{6 heteroalkyl,} C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 3 -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or a monocyclic heteroaryl, substituted or unsubstituted.

In some embodiments, ^{R 5} is ^{halogen, -CN, -OH, -OR 9,} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —N (R ⁹ ) ₂ , —C (= O) NH (R ⁹ ), C ₁ -C ₁₀ Alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, or -L ¹ -L ² -R ⁶ and L ¹ is absent, or -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH- or -S (= O) ₂ NH-, L ² is C ₁ -C ₆ alkylene, R ⁶ -CN, -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ ,- ^{_{CO 2 R 9, -C (=}} O) N (R 9) 2, substituted or unsubstituted _C 3 -C ₆ cycloalkyl, substituted or unsubstituted _C 2 -C ₆ heterocycloalkyl, a substituted or unsubstituted Monocyclic heteroaryl or substituted or unsubstituted phenyl.

In some embodiments, R ^A is -CH ₃ and both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Alternatively, each R ¹ is —CH ₃ and R ⁵ is a halogen, —CN, —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R _{^{10, -S (= O) 2}} N (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) NH (R 9) , C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cyclo Alkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or ^{a -L} 1 -L 2 -R ^6, or ^{L 1} is absent, -O -, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH- or -S (= O) ₂ NH-, L ² is C ₁ -C ₆ alkylene, and R ⁶ is substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl or It is substituted or unsubstituted phenyl.

  In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite, or prodrug thereof is described herein:

here,
Each R ¹ is independently selected from H and -CH ₃ ;
Alternatively, both R ¹ are taken together with the carbon atom to which they are attached to form cyclobutyl,
X is O or S,
X ¹ is CH or N,
R ^A is -CN or -C (= O) NH ₂ ,
R ⁵ is —CO ₂ H or —C (= O) NH ₂ .

  In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite, or prodrug thereof is described herein:

here,
Each R ¹ is independently selected from H and -CH ₃ ;
Alternatively, both R ¹ are taken together with the carbon atom to which they are attached to form cyclobutyl,
X is O,
X ¹ is CH or N,
R ^A is -CN or -C (= O) NH ₂ ,
R ⁵ is —CO ₂ H, —C (= O) NH ₂ or —C (= O) NH (CH ₃ ).

  In some embodiments, a compound of Formula (X), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite, or prodrug thereof is described herein:

here,
Each R ¹ is independently selected from H and -CH ₃ ;
Alternatively, both R ¹ are taken together with the carbon atom to which they are attached to form cyclobutyl,
X is O or S,
X ¹ is CH or N,
R ^A is —C (= O) NH ₂ ,
R ⁵ is —CO ₂ H, —C (= O) NH ₂ or —C (= O) NH (CH ₃ ).

  Throughout the specification, groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds.

  The compounds disclosed herein are selective androgen receptor modulators. In some embodiments, the compounds disclosed herein have high specificity for the androgen receptor and have desirable tissue selective pharmacological activity. Desirable tissue selective pharmacological activities include, but are not limited to, AR antagonist activity on prostate cells but not AR non-prostate cells. In some embodiments, the compounds disclosed herein are antiandrogens that exhibit negligible AR agonist activity or no AR agonist activity at all.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or a compound selected from active metabolites, tautomers, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or prodrugs of the compounds of (X) Are presented herein.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) a therapeutically effective amount of the compound is provided. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable inactive ingredient. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a tablet, a pill, a capsule, a solution, a suspension, a gel, a colloid, a dispersion, a suspension, a solvent, an emulsion, an ointment, or a lotion. .

  In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutically active agents selected from: corticosteroids, antiemetics, analgesics, anticancer agents, antiinflammatory agents, Kinase inhibitors, HSP90 inhibitors, histone deacetylase (HDAC) inhibitors.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) Provided herein a method comprising administering a compound of (IXa), or (X) to a human with an androgen receptor-mediated or androgen receptor dependent disease or condition. Be done. In some embodiments, the human has the formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) , (IX), (IXa) or (X) one or more additional therapeutically active agents have already been administered. In some embodiments, the method comprises formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) Further comprising administering one or more additional therapeutically active agents other than the compounds of (IX), (IXa), or (X).

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) And one or more therapeutically active agents other than the compounds of (IXa) or (X) are selected from: Corticosteroids, antiemetics, analgesics, anticancer agents, antiinflammatory agents, kinase inhibitors, HSP90 inhibitors, histone deacetylase (HDAC) inhibitors.

  In some embodiments, a therapeutically effective amount of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), Administering a compound of (VIIIa), (IX), (IXa) or (X), or a pharmaceutically acceptable salt or N-oxide thereof to a mammal, in a mammal Methods for treating androgen receptor mediated or androgen receptor dependent diseases or conditions are described herein. In some embodiments, the androgen receptor dependent or androgen receptor mediated disease or disorder comprises benign prostate hyperplasia, hirsutism, acne, prostate adenoma and overgrowth, androgen receptor Benign or malignant tumor cells, hyperhilarious, seborrhoea, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppression of spermatogenesis, sexual desire, cachexia, loss of appetite , Androgen replacement for age-related reduction of testosterone levels, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flush, and muscle atrophy and weakness in Kennedy's disease, skin atrophy, bone loss, anemia , Arteriosclerosis, loss of vitality, loss of health, type 2 diabetes, and abdominal fat accumulation.

  In some embodiments, a therapeutically effective amount of Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), A mammalian cancer comprising a step of administering a compound of (VIIIa), (IX), (IXa) or (X), or a pharmaceutically acceptable salt or N-oxide thereof to a mammal Methods of treatment are described herein. In some embodiments, the cancer is a hormone dependent cancer. In some embodiments, the hormone dependent cancer is an androgen receptor dependent cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is hormone refractory prostate cancer. In some embodiments, the method of treating cancer further comprises administering to the mammal at least one additional anticancer agent.

  In some embodiments, a method of treating cancer in a mammal is described herein, comprising administering a therapeutically effective amount of the compound to the mammal, wherein the compound is: Androgen receptor inverse agonist; androgen receptor antagonist; androgen receptor degrader; androgen receptor transport modulator; androgen receptor degrader; androgen receptor DNA binding inhibitor; or a combination thereof. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is hormone refractory prostate cancer. In some embodiments, the compounds are of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) , (IX), (IXa), or (X), or a pharmaceutically acceptable salt or N-oxide thereof.

  The pharmaceutical preparation described herein can be administered to a subject by multiple administration routes, which include oral, parenteral (eg, intravenous, subcutaneous, intramuscular), buccal, topical, Alternatively, transdermal routes of administration are included, but are not limited thereto. The pharmaceutical formulations described herein may be aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, solid dosage forms, powders, immediate emission formulations, sustained release formulations, fast dissolving formulations, tablets, capsules Including, but not limited to, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations. .

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are administered orally.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are administered topically. In such embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds, solvents, suspensions, lotions, lotions, gels, pastes, shampoos, scrubs, scrubs, rubs, smears It is formulated into various topically administrable compositions such as medicated sticks, medicated dressings, analgesics, creams, or ointments. Such pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives. In one aspect, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compound of (IXa) or (X) is topically administered to the skin.

  In another aspect, the compound of formula (I), (D) in the manufacture of a medicament for treating a disease, disorder or disease in which the activity of the androgen receptor contributes to the pathology and / or symptoms of the disease or disease Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or a compound of (X) The use of is described. In one embodiment, the disease or condition is any disease or condition specified herein.

  In any of the preceding aspects, in a further embodiment (a) an effective amount of Formula (I), (II), (III), (IV), (V), (VI), (VII), ( VIII), (IX), or (X) is administered systemically to a mammal and / or (b) an effective amount of the compound is orally administered to a mammal, and / or , (C) an effective amount of the compound is intravenously administered to the mammal, and / or (d) an effective amount of the compound is administered to the mammal by infusion, and / or (e) effective. An amount of the compound is administered topically to the mammal and / or (f) an effective amount is administered non-systemically or topically to the mammal.

  In any of the foregoing aspects, a further embodiment comprises a single administration of an effective amount of the compound, the aspect comprising a further embodiment comprising: (i) the compound is administered once, (ii 2.) The compound is administered to the mammal multiple times during the day, (iii) continuously or (iv) continuously.

  In any of the preceding aspects, a further embodiment comprises multiple administrations of an effective amount of the compound, which comprises the following further embodiments, wherein (i) the compound is continuous as a single dose Or intermittently, (ii) multiple dose intervals are every 6 hours, (iii) the compound is administered to the mammal every 8 hours, and (iV) the compound is every 12 hours Animals are administered and (v) compounds are administered to mammals every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily suspended or the amount of compound being administered is temporarily reduced and At the end of the drug period, administration of the compound is resumed. In one embodiment, the length of the drug holiday is different from 2 days to 1 year.

  Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or Also provided is a method of reducing AR activation in a mammal, comprising administering to the mammal with at least one compound having a structure of (X). In some embodiments, the method comprises reducing AR activation of prostate cells in a mammal. In some embodiments, the method comprises reducing AR activation of prostate cells in the mammal and not reducing AR activation of non-prostate cells. In some embodiments, the method of reducing AR activation comprises reducing the binding of androgen to the androgen receptor. In some embodiments, the method of reducing AR activation comprises reducing AR concentration.

  In some cases, the compounds of formulas (I), (Ia), (II), (III), or (III), in the manufacture of a medicament for the treatment of an androgen receptor dependent or androgen receptor mediated disease or disorder. Disclosed herein is the use of a compound of (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) . In some embodiments, the disease or condition is a prostrate cancer. In some embodiments, androgen receptor dependent or androgen receptor mediated diseases or disorders are described herein.

  In some cases, Formula (I), (Ia), (II), (III), (IV), (IV), in the prevention or treatment of an androgen receptor dependent or androgen receptor mediated disease or disorder. The use of compounds of V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is described herein. In some embodiments, androgen receptor dependent or androgen receptor mediated diseases or disorders are described herein.

  In any of the embodiments disclosed herein, the mammal is a human.

  In some embodiments, the compounds provided herein are administered to humans.

  In some embodiments, the compounds provided herein are administered orally.

  In some embodiments, the compounds provided herein are used to attenuate, reduce or eliminate the activity of the androgen receptor.

  Packaging material, and formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIa), in the packaging material IX), (IXa), or (X), and a compound or composition, or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide thereof, pharmaceutical Active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate, to attenuate, reduce or eliminate the effects of the androgen receptor, or A product is provided that includes a label indicating that it is to be used for the treatment, prevention or amelioration of one or more symptoms of a disease or disorder that would benefit from a reduction or elimination of activity.

  Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description, and therefore the detailed description and the specific examples provide specific embodiments. Although shown, it is given for illustrative purposes only.

  The androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily. Within this large family of proteins, only five spinal steroid receptors are known, including androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor and mineralocorticoid receptor. AR is a soluble protein that functions as a transcription factor in cells. AR function is regulated by androgen binding. Anthrogens initiate sequential structural changes of the receptor that affect receptor-protein interactions and receptor-DNA interactions.

  AR is primarily expressed in androgen target tissues such as prostate, skeletal muscle, liver and central nervous system (CNS) with the highest expression levels observed in prostate, adrenal and epididymis. AR can be activated by binding of endogenous androgens, including testosterone and 5α-dihydrotestosterone (5α-DHT).

  The androgen receptor (AR), located at Xq11-12, is a 110 kD nuclear receptor that, when activated by androgen, mediates transcription of target genes that regulate growth and differentiation of prostate epithelial cells. Similar to other steroid receptors, the released AR is mainly located in the cytoplasm and is related by a complex of heat shock proteins (HSPs) through its interaction with the ligand binding domain. Upon agonist binding, the AR undergoes a series of structural changes. That is, heat shock proteins break the relationship from AR, and the transformed AR undergoes dimerization, phosphorylation and translocation to the nucleus. It is mediated by nuclear translocation signals. The displaced receptor then binds to the androgen response element (ARE). The androgen response element (ARE) is characterized by a half-site consensus sequence 5'-TGTTCT-3 'of six nucleotide sites spaced by three random nucleotides, at the promoter or enhancer site of the AR gene target To position. Enhancement of the other transcriptional co-regulators (including coactivator and repressive complement) and the mechanism of transcription further ensure transactivation of AR-regulated gene expression. All these processes are initiated by ligand induced conformational changes in the ligand binding region.

  AR signaling is important for the development and maintenance of male reproductive organs including the prostate so that inherited males harboring AR mutations of designed function and loss of mice with AR defects do not develop prostate or prostate cancer. This dependence of prostate cells on AR signaling continues even in malignant transformation. Androgen depletion (here, using GnRH agonists) continues to be central to the treatment of prostate cancer. However, androgen depletion is usually effective for a limited duration. Also, prostate cancer develops to restore its ability to grow despite circulating (low levels) androgen. As a treatment option for castration resistant prostate cancer (CRPC), docetaxel should not be considered the only drug that has been shown to prolong survival. A minority of CRPCs bypasses the requirement for AR signaling, the majority of CRPC, but interestingly, AR signaling, often referred to as "androgen independent prostate cancer" or "hormone refractory prostate cancer" Hold its lineage dependence on

  Prostate cancer is the second most common cause of cancer death in men in the United States, with approximately one in six American men being diagnosed with disease during his lifetime. Treatment aimed at eradicating tumors usually spreads to remote plasma sites and subsequently fails in 30% of men with recurrent disease, the first manifest as elevation of prostate specific antigen (PSA). Given that prostate cancer cells are dependent on the androgen receptor (AR) for their growth and survival, these men are block makers of drug-treated testosterone (eg, GnRH agonists), alone. Or antagonize the effects of residual testosterone in combination with an antiandrogen (eg, bicalutamide). The approach is effective as evidenced by the reduction and regression of PSA levels in the visible tumor (if present); however, this causes most patients to eventually die and "castration resistant" prostate cancer (CRPC) As re-growth continues. Recent studies on the molecular basis of CRPC suggest that CRPC is the key mechanism for AR signaling and acquired resistance to be elevated levels of AR proteins (Nat. Med, 2004, 10, 33-39) It demonstrated that it continued to depend. Targeting drugs with activity in hormone-sensitive and resistant castration-resistant prostate cancer, AR has great promise for the treatment of this deadly disease.

  Antiandrogens help treat prostate cancer during its early stages. However, prostate cancer often progresses to a hormone refractory condition in which the disease has progressed in the presence of continuous androgen deprivation or antiandrogen therapy. The case of antiandrogen withdrawal syndrome was also reported after prolonged treatment with antiandrogen. Antiandrogen withdrawal syndromes are generally observed clinically and are defined in terms of regression of observed tumors or relief of symptoms upon cessation of antiandrogen treatment. The consequences of the ability of these antiandrogens to exert AR mutation acceptance and antagonism may at least partially account for this phenomenon. For example, hydroxyflutamide and bicalutamide act as AR agonists in T877A and W741L / W741C AR mutants, respectively.

  In the setting of prostate cancer cells rendered "castration resistant" through overexpression of AR, it demonstrates that certain antiandrogenic compounds, such as bicalutamide, have no antagonist activity at all, instead , Slightly have agonist activity (Science, 2009, May 8; 324 (5928): 787-90). This agonist activity helps to explain the clinical observation called antiandrogen withdrawal syndrome. About 30% of men who progress on AR antagonists experience a decrease in serum PSA (J Clin Oncol (1993). 11 (8): pages 1566-72), thereby stopping treatment.

  Given the central role of AR in the development and progression of prostate cancer, these compounds modulate other important pathways in prostate cancer, including but not limited to alone or in combination herein Other agents that may not be used, and which are useful in the treatment of prostate cancer, including but not limited to those that target IGF1R, PI3K / AKT / mTOR axis, HSP90, or histone deacetylase .

  AR-related diseases or conditions include benign prostatic hypertrophy, hirsutism, acne, adenoma and hyperplasia of the prostate, androgen androgen receptor, hyperpilosity, seborrhea, endometriosis, polycystic ovary syndrome Benign or malignant cells including, but not limited to: alopecia, hypogonadism, osteoporosis, suppression of spermatogenesis, suppression of spermatogenesis, libido, cachexia, loss of appetite, age androgen replacement-related reduced testosterone levels, prostate Cancer, breast cancer, endometrial cancer, uterine cancer, hot flush, muscle atrophy and weakness in Kenedy's disease, skin atrophy, bone loss, anemia, arteriosclerosis, cardiovascular disease, loss of energy, loss of happiness , Type 2 diabetes and abdominal fat accumulation.

  In some embodiments, the compounds disclosed herein inhibit AR nuclear translocation, DNA binding to androgen response elements, and coactivator recruitment. In some embodiments, the compounds disclosed herein exhibit no agonist activity on AR overexpressing prostate cancer cells.

  In some embodiments, the compounds disclosed herein are used to treat chemotherapy-treated mammalian naive cancer.

  In some embodiments, the compounds disclosed herein are used to treat a mammal's depressed cancer, wherein the mammal has been treated for cancer with at least one anti-cancer agent. In certain embodiments, the prostate cancer is a stimulant resistant prostate cancer. In certain embodiments, the prostate cancer is bicalutamide resistant prostate cancer.

(Compound)
The compounds of the formula (I) are compounds of the formulas (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) (IXA) and (X) are pharmaceutically acceptable salts, prodrugs and derivatives thereof including pharmaceutically acceptable solvates, such as androgen receptor modulators, AR inverse agonists, AR antagonists, AR digs It is useful for the treatment of diseases of an androgen receptor dependent or androgen receptor mediated disease, disorder or condition which is a degrader, AR transport modulator and / or AR DNA binding inhibitor.

  In one aspect, provided herein is a compound of formula (I)

Or a pharmaceutically acceptable salt, solvate, N oxide, or prodrug thereof. Wherein ring A is monocyclic heteroaryl, bicyclic heteroaryl or naphthyl; m is 0, 1, 2, 3 or 4 and each R ^A is independently H, halogen _{^{, -CN, -NO 2, -OH,}} -OR 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10 -N (R 11) S (= O) 2 R _{^{10, -S (= O) 2}} N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) N (R ⁹ ) ₂ , substituted or C ₁ -C ₆ alkyl, unsubstituted, substituted or C ₁ -C ₆ fluoroalkyl unsubstituted, substituted or C ₁ -C ₆ fluoroalkoxy aryl, substituted or substituted Or substituted or substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, unsubstituted C ₁ -C ₆ heterocycle R ¹ is unsubstituted C ₁ -C ₆ alkoxy, substituted C ₂ -C ₁₀ heterocycloalkyl, substituted or phenyl group, or substituted or unsubstituted monocyclic heteroaryl; R ¹ is H, —OH, respectively Independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl; or both R ¹ are Embedded with a carbon atom which is attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, and R ² is H respectively , or both ^{R 2} s, -C (= S) - or -C - (= O) - obtained with carbon that is bound to form a; ^{R 3} are each H There, or both ^{R 3} are, -C (= S) - or -C (= O) - when being combined to form a resulting together with the carbon; ^{R 3} is each H; or both R ³ is obtained with the carbon attached to form —C (SS) — or —C (= O) —, provided that each R ² is not H when R ³ is H; B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; n is 0, 1, 2, 3 or 4 and R ⁴ is H, halogen, -CN, -NO, respectively. ² , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S ( _{^{= O) 2 N (R 9}} ) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -O _{^{O 2 R 10, -N (R}} 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl R ⁵ is independently selected from substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ heteroalkyl; Substituted or unsubstituted C _{2 to} C ₁₀ alkyl substituted or unsubstituted C _{2 to} C ₁₀ fluoroalkyl, substituted or unsubstituted C _{2 to} C ₁₀ alkoxy, substituted or unsubstituted C _{2 to} C ₁₀ fluoroalkoxy, substituted Or unsubstituted C ₂ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterofluoroalkyl or -L ¹ -L ² -R ⁶ ; L ¹ is absent or -O-, -S-, -S (= O )-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O)-, -OC (= O) NH-, -NHS (= O) ₂ -Or-S (= O) ₂ NH-,
L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene; R ⁶ is a halogen, — _{^{CN, -NO 2, -OH, -OR}} 9, -SR 9, -S (= O) R 10, -S (= O) 2 R10, -N (R11) S (= O) 2 R 10, - _{^{S (= O) 2 N (}} R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R 10, -N (R 9) 2 And —C (OO) N (R ⁹ ) ₂ , —OC (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) N (R ⁹ ) ₂ , and —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted Monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted naphthyl, wherein R ⁹ is H, substituted or unsubstituted C ₁ or -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, optionally substituted heteroaryl, _-C 1 -C ₄ Arukeren - (substituted Other _C 3 _{-C 10} cycloalkyl unsubstituted), _- C 1 -C ₄ Arukeren - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ Arukeren - (substituted or unsubstituted Two R ⁹ groups independently selected from substituted aryl) and linked to the same N atom are —C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl) or substituted or unsubstituted R ¹⁰ is optionally taken together with the N atom linked to form a C ₂ -C ₁₀ heterocycloalkyl, R ¹⁰ is optionally substituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, _-C 1 -C ₄ Arukeren - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ Arukeren - (substituted or unsubstituted Selected from C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkenene (substituted or unsubstituted aryl) and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), ¹¹ is H or C ₁ -C ₄ alkyl.

For any and all embodiments, substituents are selected from among the listed subsets of alternatives. For example, in some embodiments, both R ¹ , together with the carbon atom to which they are attached, are substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. For example, in some embodiments, both R ¹ are obtained together with the carbon atom that is attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments, both R ₁ are obtained together with the carbon atom that is attached to form a substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, both R ¹ are obtained together with the carbon atom to which they are attached to form cyclopropyl. In some embodiments, both R ¹ are obtained together with the carbon atom to which it is attached to form cyclobutyl. In some embodiments, both R ¹ are obtained together with the carbon atom to which they are attached to form cyclopentyl. In some embodiments, both R ¹ are obtained together with the carbon atom to which they are attached to form cyclohexyl. In some embodiments, each R ¹ is independently selected from H, -OH, C ₁ -C ₆ alkyl, and C ₁ -C ₆ fluoroalkyl. In some embodiments, each R ¹ is independently selected from H, -CH ₃ and CF ₃ . In some embodiments, R ¹ is -CH ₃ . In some embodiments, both R ¹ are taken together with the carbon atom to which they are cyclobutyl or to which each R ¹ is attached to form —CH ₃ .

In some embodiments, both R ² are obtained together with the carbon attached to form —C (CS) or —C (= O) —, and both R ³ are , -C- (= O) is obtained together with the carbon that is bound to form. In some embodiments, both R ² are obtained together with the carbon attached to form -C-(= S); both R ³ form -C (= O) It is obtained together with the carbon that is attached to it.

  In some embodiments, ring A is linked by C-linked monocyclic heteroaryl, C-linked bicyclic heteroaryl or naphthyl. In some embodiments, ring A is a C-linked monocyclic heteroaryl. In some embodiments, ring A is a C-linked monocyclic 5-membered or 6-membered heteroaryl. In some embodiments, ring A is a C-linked monocyclic 6-membered heteroaryl. In some embodiments, ring A is an N-containing heteroaryl.

In some embodiments, both R 1 are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl; both R ² are It is obtained together with the carbon which is attached to form (= S); both R ³ are obtained together with the carbon which is attached to form -C (= O); Ring A is N-containing monocyclic heteroaryl or N-containing bicyclic heteroaryl; R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R, respectively ^{_{10, -N (R 11) S}} (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, - CO ₂ R ⁹ and ^{-C (= O) N (R} 9) 2, substituted or unsubstituted _C 1 -C ₆ alkyl, optionally Substituted C ₁ -C ₆ fluoroalkyl, and optionally substituted C ₁ -C ₆ fluoroalkoxy, and optionally substituted C ₁ -C ₆ alkoxy (single rings that are optionally substituted or optionally substituted phenyl A heteroaryl of the formula), optionally substituted C ₁ -C ₆ fluoroalkyl and optionally substituted C ₁ -C ₆ fluoroalkoxy and optionally substituted C ₁ -C ₆ alkoxy (optionally substituted phenyl Or an optionally substituted monocyclic heteroaryl) independently.

In some embodiments, both R ¹ are obtained together with the carbon atom to which they are attached to form a cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl; ring A is a pyridinyl, pyrimidinyl group An N-containing monocyclic heteroaryl selected from pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, isothiazolyl, triazolyl and tetrazolyl.

  In some embodiments, ring A is pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl. In some embodiments, ring A is pyridinyl.

  In some embodiments,

Is

Or in some embodiments,

Is

It is.

In some embodiments, ring A is mono-substituted by R ^A. In some embodiments, ring A is di-substituted by R ^A. In some embodiments, ring A is tri-substituted by R ^A. In some embodiments, ring A is substituted by -CN and at least one additional R ^A. In some embodiments, ring A is substituted with -CN and zero, one or two additional R ^A. In some embodiments, ring A is substituted by -CN and one or two additional ^RA . In some embodiments, ring A is substituted by -CN and one additional R ^A.

In some embodiments, ring A is pyridinyl and R ^A is H, halogen, -CN, -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R), respectively. ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _1- It is independently selected from C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, both R ¹ are obtained together with the carbon atom attached to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; ring A is quinolinyl, isoquinolinyl, quinazolinyl, Quinoxalinyl, Naphthyridinyl, Indolyl, Indazolyl, Benzoxazolyl, Isoxazolyl, Benzofuranyl, Benzothiazolyl, Benzothiazolyl, Benzoimidazolyl, Purinyl, Cinnolinyl, Phthalazinyl, Pteridinyl, Pyridopyrimidinyl, Pyrazolopyrimidinyl, Azaindolyl, Azazolopyridinyl, Thiazolo N-containing bicyclic heteroaryl, selected from pyrimidinyl, triazolopyridazinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyl, pyrrolopyrimidinyl R ^A is H, halogen, -CN, -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) N (R) ⁹⁾ _2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 fluoroalkoxy, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or It is independently selected from unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl.

  In some embodiments, ring A is an N-containing bicyclic heteroaryl selected from quinoliquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, triazolopyridazinyl and pyrrolopyrimidinyl.

  In some embodiments, ring A is [1,2,4] triazolo [4,3-b] pyridazinyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl; R ⁴ is H, halogen, -CN, -NO ₂ and -OH substituted or unsubstituted C ₁ -C ₆ alkyl, respectively , Substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ hetero R ⁵ is independently selected from alkyl; substituted or unsubstituted C ₂ -C ₁₀ alkyl substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkoxy, substituted or unsubstituted _C 2 _{-C 10} fluoroalkoxy, substituted or unsubstituted _C 2 _{-C 10} heteroalkyl, substituted or unsubstituted _C 2 _{-C 10} Heterofuruo Is alkyl or ^-L 1 ^-L 2 -R ^{6; if L 1} is absent, -O -, - S -, - S (= O) -, - S (= O) 2 -, - NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHS (= O) _2- , or -S (= O) ₂ NH-; L ² is substituted Or unsubstituted C ₁ -C ₆ alkylene substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or substituted or unsubstituted C ₁ -C ₆ heteroalkylene; R ⁶ is halogen, -CN, -NO _{2 ^{, -OH, -OR 9, -SR 9}} , -S (= O) R 10, -S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O _{^{) R 10, -CO 2 R 9}} , -N (R 9) 2, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 _{-C 10} cycloalk Le, a substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or It is unsubstituted phenyl or substituted or unsubstituted naphthyl.

In some embodiments, ring B is phenyl or monocyclic heteroaryl; R ⁴ is H, halogen, -CN, -NO ₂ and -OH substituted or unsubstituted C 1 -C 4 alkyl, substituted, respectively Or independently selected from unsubstituted C ₁ -C ₄ fluoroalkyl, substituted or unsubstituted C ₁ -C ₄ fluoroalkoxy and substituted or unsubstituted C ₁ -C ₄ alkoxy; R ⁵ is substituted or unsubstituted of _C 2 _{-C 10} alkyl substituted or unsubstituted _C 2 _{-C 10} fluoroalkyl, substituted or unsubstituted _C 2 _{-C 10} alkoxy, substituted or unsubstituted _C 2 _{-C 10} fluoroalkoxy, substituted or unsubstituted C ₂ -C ₁₀ heteroalkyl, is _C 2 _{-C 10} heteroalkyl fluoroalkyl or ^-L 1 ^-L 2 -R ⁶ substituted or unsubstituted; ^{L 1} is Or not resident, -O-, or -C (= O) a NH-; ^{L 2} is a substituted or unsubstituted _C 1 -C ₆ alkylene, conversion or _C 1 -C ₆ fluoroalkylene or substituted unsubstituted or certain unsubstituted _{C1-C 6} ^{heteroalkylene;} R ₆ ^{is, -CN, -NO 2, -OH,} -OR 9, -SR 9, -S (= O) R 10, -S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ and —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C 10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In some embodiments, L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene; R ⁶ is —CN, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₁ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

In some embodiments, R ⁶ is substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted Or bicyclic heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted naphthyl.

In some embodiments, L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene; R ⁶ is —CN, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ or —C (= O) N (R ⁹ ) ₂ ; R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, respectively , Substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C-C alkylene- (substituted or unsubstituted C -C heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), or Two R9 groups bonded to the same N atom are Obtained together with the N atom to form a _C 2 _{-C 10} heterocycloalkyl substituted or ^{unsubstituted, R 10} is a substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl) , -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl).

  In some embodiments, provided is a compound of formula (Ia), or a pharmaceutically acceptable salt or N-oxide thereof:

here,
Ring A is monocyclic heteroaryl, bicyclic heteroaryl or naphthyl; m is 1, 2, 3 or 4 and each R ^A is independently H, halogen, -CN, _{^{-NO 2, -OH, -OR 9,}} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -N (R 11) S (= O) 2 R 10, - _{^{S (= O) 2 N (}} R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O ) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ heteroalkyl; both R ¹ is a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted C ₂ -C ₆ heterocycle R ¹ is obtained from H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ fluoroalkyl, respectively, together with the carbon atoms attached to form alkyl; X is S or O; ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; n is 0, 1, 2, 3 or And R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , respectively. _{^{-N (R 11) S (=}} O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R ⁹ , —OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —OC (OO) N (R ⁹ ) ₂ , _{^{-NR 11 C (= O) N}} (R 9) 2, -NR 11 C (= O) R 10, -NR 11 C (= O) OR 10, C 1 -C 6 _alkyl, C 1 -C ₆ fluoro Alkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ heteroalkyl, R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ; L ¹ does not exist, -O-, -S-, -S (= O)-, -S (= O) 2-, -NH-, -C (= O)-, -C (= O) NH , -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O -, - OC (= O ) NH -, - NHS (= O) 2 -, or -S _{(= O)} is 2 NH-, ^{L 2} is _C 1 -C _{6 alkylene,} C 1 -C ₆ full Is Roarukiren or _C 1 -C ₆ heteroalkylene; ^{R 6} is _{^{halogen, -CN, -NO 2, -OH,}} -OR 9, -SR 9, -S (= O) R 10, -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ¹⁰ , —CO ₂ R ⁹ , —OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —C (= O) N (R ⁹ ) ₂ , —OC (= O) N (R ⁹ ) ₂ , — NR ¹¹ C (CO) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl And C ₁ -C ₆ heteroalkyl substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ hetero R ⁷ is substituted or unsubstituted cyclocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl; Substituted monocyclic C ₂ -C ₆ heterocycloalkyl, or substituted or unsubstituted monocyclic heteroaryl; R ⁹ represents H, C ₁ -C ₆ alkyl or C ₁ -C ₆ , respectively. Heteroalkyl and C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 -C ₆ cycloalkyl, _-C 1 -C ₄ alkylene - ( Conversion or unsubstituted monocyclic _C 2 -C ₆ heterocycloalkyl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted phenyl, and _-C 1 -C ₄ alkylene - (substituted or unsubstituted, mono- cyclic independently selected from heteroaryl; two R9 groups attached to or the same N atom may be linked to form a C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or C ₃ -C ₆ cycloalkyl, substituted or monocyclic C ₂ -C ₆ heteroalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted -C ₁ -C ₄ alkenyl Emissions - (substituted or unsubstituted _C 3 -C ₆ cycloalkyl), _- C 1 -C ₄ Arukeren - _(C 2 -C ₆ heterocycloalkyl monocyclic substituted or unsubstituted), _- C 1 -C ₄ R ¹¹ is H or C ₁ -C ₄ alkyl, or alkyren- (substituted or unsubstituted phenyl) or —C ₁ -C ₄ -alkene- (substituted or unsubstituted monocyclic heteroaryl);

In some embodiments, both R ¹ are obtained together with the carbon atom that is attached to form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl; X is S; A is N-containing monocyclic heteroaryl; R ^A is H, halogen, -CN, -NO ² , -OH, -S (= O) ² R ¹⁰ , -N (R ¹¹ ) S, respectively _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9 and -C (= O) independently selected from N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy and C ₁ -C ₆ alkoxy;
Ring B is phenyl or monocyclic heteroaryl.

In some embodiments, both R ¹ are obtained together with the carbon atom attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; ring A is pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl is there.

In some embodiments, ring A is pyridinyl and R ^A is H, halogen, -CN, -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ), respectively. ^{_{selection) 2, -C (= O)}} N (R 9) 2, C 1 -C 6 _alkyl, C 1 -C _{6 fluoroalkyl,} independently from C 1 -C ₆ fluoroalkoxy and _C 1 -C ₆ alkoxy Be done.

In some embodiments, R ^A is H, halogen, -CN, -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy and C ₁ -C ₆ alkoxy independently selected. In some embodiments, each R ^A is H, halogen, -CN, -OH, -C (= O) N (R 9) 2, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C independently selected from ₁ -C ₄ fluoroalkoxy and _C 1 -C ₄ alkoxy. In some embodiments, each R ⁶ is H, F, Cl, CN, -OH, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCF ₃ , -COCH ₃ , -OCH ₂ CH ₃ It is selected independently from

In some embodiments, ring B is phenyl and R ⁵ is -L ¹ -L ² -R ⁶ ; L ^{1 is} absent or -O-, -S-, -S (= O)- , -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHS (= O) _2-, or- S _{(= O)} is 2 NH-; ^{L 2} is an _C 1 -C _{6 alkylene,} C 1 -C ₆ fluoroalkylene or _C 1 -C ₆ heteroalkylene; ^{R 6} is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= _{^{O) R 10, -CO 2 R}} 9, -N (R 9) 2, -C (= O) N (R 9) 2, substituted or unsubstituted _C 3 -C ₆ cycloalkyl, substituted or Substituted C ₂ -C ₆ heterocycloalkyl, a substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted phenyl.

In some embodiments, ring B is phenyl and each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ R ⁵ is independently selected from -C ₄ fluoroalkoxy and C ₁ -C ₄ alkoxy; R ⁵ is -L ¹ -L ² -R ⁶ ; L ^{1 is} absent, -O-, or -C (= L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is —CN, —NO ₂ , —OH, — OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -C (= O) R ¹⁰ , -CO ₂ R ⁹ and -C (= O) N (R) ^{9) 2,} substituted or unsubstituted _C 3 -C ₆ cycloalkyl, substituted or Is an unsubstituted C ₂ -C ₆ heterocycloalkyl, heteroaryl, or substituted or unsubstituted phenyl monocyclic substituted or unsubstituted.

In some embodiments, L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene; R ⁶ is —CN, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted phenyl.

In some embodiments, R ⁶ is substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted It is phenyl.

In some embodiments, when R ⁶ is substituted, R ⁶ is halogen, -CN, -NH ₂ , -NH (CH ₃ ), -N (CH ₃ ) ₂ , -OH, -CO _{2 H, -CO 2 (C 1 -C} 4 _{alkyl), - C (= O)} C 1 -C 4 _{alkyl, -C (= O) NH 2} , -C (= O) NH (C 1 -C 4 alkyl ), -C (= O) N (C ₁ -C ₄ alkyl) ₂ , -S (= O) ₂ NH ₂ , -S (= O) ₂ NH (C ₁ -C ₄ alkyl), -S (= O) ₂ N (C ₁ -C ₄ alkyl), C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, C ₁ -C ₄ alkoxy , C ₁ -C ₄ fluoroalkoxy, -S-C ₁ -C ₄ alkyl, or -S (= O) ₂ C ₁ -C ₄ It is substituted with one or two groups selected from In some embodiments, when R ⁶ is substituted, R ⁶ is halogen, —CN, —OH, —CO ₂ (C ₁ -C ₄ alkyl), —C (= O) C ₁ -C ₄ alkyl and _{-C (= O) NH 2,} -C (= O) NH (C 1 -C 4 _{alkyl) -C (= O) N (} C 1 -C 4 _{alkyl) 2,} C 1 -C ₄ alkyl, One or two independently selected from C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy It is substituted by a group.

In some embodiments, L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene; and R ⁶ is a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl. In some embodiments, L ¹ is absent, -O-, or -C (= O) NH-; L ² is C ₁ -C ₆ alkylene; R ⁶ is substituted or unsubstituted a C ₂ -C ₆ heterocycloalkyl. In some embodiments, L ^{1 is} absent, -O-, or -C (C = O) NH-. In some embodiments, R ⁶ is a substituted or unsubstituted C ₃ -C ₆ heterocycloalkyl. In some embodiments, R ⁶ is a substituted or unsubstituted N-containing C ₂ -C ₆ heterocycloalkyl.

In some embodiments, ring B is phenyl and each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted R ¹ is independently selected from C ₁ -C ₄ fluoroalkyl, substituted or unsubstituted C ₁ -C ₄ fluoroalkoxy, and substituted or unsubstituted C ₁ -C ₄ alkoxy; R ⁵ is —L ¹ -R ⁷ Or L ¹ does not exist, -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O -, - OC (= O) NH -, - NHS (= O) 2 - or -S _{(= O)} is 2 NH-,; ^{R 7} , A substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl or substituted or unsubstituted monocyclic heteroaryl;

In some embodiments, L ² is substituted or unsubstituted C ₁ -C ₆ alkylene; in some embodiments, L ² is C ₁ -C ₄ alkylene. In some embodiments, ^{L 2} is _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH ₂ CH _2- or -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH _2- . In some embodiments, ^{L 2} is _{-CH 2 -, - CH 2 CH} 2 -, - CH 2 CH 2 CH 2, or _{CH 2 CH 2 CH 2 CH 2} - is.

In some embodiments, each R ⁴ is independent of H, halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy and C ₁ -C ₄ alkoxy To be chosen.

In some embodiments, R ⁵ is -L ¹ -R ⁷ .

In some embodiments, L ¹ is absent or -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)- , -C (= O) NH-, or -S _{(= O)} is 2 NH-. In some embodiments, L ¹ is absent. In some embodiments, L ¹ is —O—, —S—, —S (= O) —, —S (= O) ₂ —, —NH—, —C (= O) —, —C (= O) NH— or —S (= O) ₂ NH—. In some embodiments, L ¹ is absent. In some embodiments, L ¹ is -O-. In some embodiments, L ¹ is absent. In some embodiments, L ¹ is —C (C = O) NH—.

In some embodiments, R ⁵ is -L ¹ -R ⁷ . L ¹ is —O—, —S—, —S (= O), —S (= O) ₂ —, —NH—, —C (= O) —, —C (= O) NH— or — S _{(= O)} 2 is NH-; ^{R 7} is a substituted or unsubstituted monocyclic _C 2 -C ₆ heterocycloalkyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, when R ⁷ is substituted, R ⁷ is halogen, —CN, —NH ₂ , —NH (CH ₃ ), —N (CH ₃ ) ₂ , —OH, —CO ₂ H , _-CO 2 _(C 1 -C _{4 alkyl), - C (= O)} C 1 -C 4 alkyl and _{-C (= O) NH 2,} -C (= O) NH (C 1 -C 4 alkyl) , -C (= O) N (C ₁ -C ₄ alkyl) ₂ , -S (= O) ₂ NH ₂ , -S (= O) ₂ NH (C ₁ -C ₄ alkyl), -S (= O ) ₂ N (C ₁ -C ₄ alkyl) ₂ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, C ₁ -C ₄ alkoxy , _C 1 -C ₄ fluoroalkoxy, _-S-C 1 -C ₄ alkyl or _{-S (= O) 2 C 1} -C 4 A It is substituted by one or two groups selected independently from kill. In some embodiments, when R ⁷ is substituted, R ⁷ is halogen, —CN, —OH, —CO ₂ (C ₁ -C ₄ alkyl), —C (= O) C ₁ -C _{4 alkyl, -C (= O) NH 2} , -C (= O) NH (C 1 -C 4 alkyl), - C (= O) N (C 1 -C 4 _{alkyl) 2,} C 1 -C ₄ alkyl , One or two independently selected from C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ fluoroalkoxy Substituted by one group.

In some embodiments, R ⁵ is -L ¹ -R ⁷ . When L1 is absent, -O-, -S-, -S (= O), -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH or -S _{(= O)} is 2 NH-; ^{R 7} is a monocyclic heteroaryl substituted or unsubstituted.

  In some embodiments, the compound of Formula (I) or Formula (Ia) has the structure of Formula (II).

  In some embodiments, the compound of Formula (Ia) has the structure of Formula (II)

Have, where

Is

And
m is 2 and
In one R ^A , -CN, -NO ² , -S (= O) ² R 10, -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -CO ₂ R ⁹ Or -C (= O) N (R ⁹ ) ₂ ; and in the other R ^A , H, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ Fluoroalkoxy or C ₁ -C ₆ alkoxy;
n is 0 or 1;
Each R ⁴ is independently from H, halogen, -CN, -NO ₂ , OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, and C ₁ -C ₆ alkoxy Selected and
R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ; L ^{1 is} absent, -O-, or -C (= O) NH-; L ² is C _1- C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —N (R ⁹ ) ² , —C (= O) N (R ⁹ ) ₂ , substitution Or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, or substituted or unsubstituted phenyl; R ⁷ It is, C ₂ -C ₆ heterocycloalkyl monocyclic substituted or unsubstituted or substituted, Others are monocyclic heteroaryl unsubstituted.

  In some embodiments,

Is

And one R ^A is -CN and the other R ^A is H, halogen, -OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy or C ₁ -C ₄ is alkoxy; each ^{R 4} is, H, halogen, _-OH, C 1 -C _{4 alkyl,} C 1 -C _{4 fluoroalkyl,} C 1 -C ₄ fluoroalkoxy, and _C 1 -C ₄ It is independently selected from alkoxy. R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ; L ^{1 is} absent, -O-, or -C (= O) NH-; L ² is C _1- C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ —C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted phenyl; R ⁷ is a substituted or unsubstituted single ring C ₂ -C ₆ heterocycloalkyl of the formula or a substituted or unsubstituted monocyclic, Heteroaryl.

  In some embodiments, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof,

here,
Ring A is bicyclic heteroaryl or naphthyl;
m is 0, 1, 2 or 3;
R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R _{^{11) S (= O) 2}} R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, - N (R ⁹ ) ₂ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C _{1 to} C ₆ alkyl, substituted or unsubstituted C _{1 to} C ₆ fluoroalkyl, substituted or unsubstituted C ₁ — C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ hetero Cycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heterocyclyl Independently selected from aryl;
R ¹ is independently selected from H, -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, respectively Being
Or both of R ¹ are taken together with the carbon atom which is attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, Each R ² is H;
Alternatively both R ² are obtained together with the carbon attached to form -C (= S)-or -C-(= O);
R ³ is each H; or both R ³ are taken together with the carbon that is attached to form —C (= S) — or —C — (= O) —; R ³ is When each is H, R 2 is not defined as H;
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl; n is 0, 1 or 2.
R ⁴ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R _{^{11) S (= O) 2}} R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, - OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (OO) N (R ₉ ) ₂ , -OC (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl , substituted or _C 1 -C ₆ fluoroalkoxy unsubstituted, substituted or unsubstituted _C 1 -C ₆ alkoxy, substituted or unsubstituted _C 1 -C It is independently selected from heteroalkyl;
R ⁵ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹⁾ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ¹⁰ , -CO ₂ R ⁹ , -OCO ² R ¹⁰ and -N (R ⁹ ) ₂ that are -C (= O) N (R ⁹ ) ₂ , -OC (= O) N (R ⁹ ) ₂ and -NR ¹¹ C (= O) N ( R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoro alkyl, substituted or unsubstituted _C 1 _{-C 10 fluoroalkoxy,} C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 _{-C 10} heteroar- Is Kill or ^{-L 1 -L 2 -R 6; L} 1 absent, -O -, - S -, - S (= O) -, - S (= O) 2 -, - NH -, - C (= O), —C (= O) NH—, —NHC (= O) —, —NHC (= O) O—, —NHC (= O) NH—, —C (= O) O—, -OC (= O) -, -OC (= O) O -, - OC (= O) NH -, - NHS (= O) 2 -, or -S _{(= O)} 2 is NH-; ^{L 2} Is a substituted or unsubstituted C ₁ -C ₆ alkylene substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene; R ⁶ is a halogen, —CN, _{^{-NO 2, -OH, -OR 9,}} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -N (R 11) S (= O) 2 R 10, - _{^{S (= O) 2 N (}} R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R 10, -N (R 9) 2 _{^{, -C (= O) N (}} R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, -NR 11 C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ hetero alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted Or unsubstituted phenyl, or substituted or unsubstituted naf There is Le;
R ⁹ represents H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkenene (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl ), -C ₁ -C ₄ alkenylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkenylene (substituted or unsubstituted aryl), and C ₁ -C ₄ alkylene- ( Independently selected from substituted or unsubstituted heteroaryl), or
Two R ⁹ groups linked to the same N atom are obtained together with the N atom linked to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl , Substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkenene (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl),- C ₁ -C ₄ alkenylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkenylene- (substituted or unsubstituted aryl), or -C-C ₄ alkylene- (substituted or non-substituted Is substituted heteroaryl;
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments, ring A is quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzoxazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoimidazolyl, purinyl, cinnorinyl, phthalazinyl, pteridinyl, pyri. It is selected from dopyrimidinyl, pyrazolopyrimidinyl, azaindolyl, ilazolopyridinyl, thiazolopyrimidinyl, triazolopyridazinyl, thiazolopyridinyl, pyridothienyl, pyrimidiothienyl, pyrrolopyrimidinyl and naphthyl.

  In some embodiments, ring A is selected from quinoliquinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, triazolopyridazinyl, pyrrolopyrimidinyl and naphthyl.

  In some embodiments, ring A is [1,2,4] triazolo [4,3-b] pyridazinyl.

  In some embodiments, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof,

Here, ring A is a 5-membered ring heteroaryl,
m is 0, 1, 2 or 3;
R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R _{^{11) S (= O) 2}} R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or Unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted It is independently selected from monocyclic heteroaryl of conversion;
R ¹ is independently selected from H, -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, respectively To be done;
Or both of R ¹ are taken together with the carbon atom which is attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl,
R ² is each H; or both R ² are obtained together with the carbon attached to form —C (CS) — or —C — (= O);
R ³ is each H; or both R ³ are taken together with the carbon that is attached to form —C (= S) — or —C — (= O) —; R ³ is When each is H, R ² is not defined as H;
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
R ⁴ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R _{^{11) S (= O) 2}} R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, - OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , -OC (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl , _C 1 -C ₆ fluoroalkoxy substituted or unsubstituted, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted _C 1 -C ₆ Terrorism alkyl;
R ⁵ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ^{11) _{) S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , -OC (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) N (R ⁹ ) ₂ ) —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted _C 1 _{-C 10} fluoroalkoxy, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 -C ₁ Heteroalkyl or ^-L 1 ^-L 2 ^-R 6; absent ^{1 L, -O -, - S} -, - S (= O) -, - S (= O) 2 -, - NH -, - C (= O), -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-,- OC (= O) -, - OC (= O) O -, - OC (= O) NH -, - NHS (= O) 2 -, or -S _{(= O)} 2 is NH-; ^{L 2} is R ⁶ is a halogen, -CN,-substituted or unsubstituted C ₁ -C ₆ alkylene substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or substituted or unsubstituted C ₁ -C ₆ heteroalkylene; _{^{NO 2, -OH, -OR 9,}} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -N (R 11) S (= O) 2 R 1 _{^{, -S (= O) 2 N}} (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R 10, -N (R 9 _{^{) 2, -C (= O)}} N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, -NR 11 C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic Heteroaryl, substituted or unsubstituted phenyl, or substituted or unsubstituted Of naphthyl;
R ⁹ represents H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cyclo, respectively Alkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkenene (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ Arukeren - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ Arukeren - (substituted or unsubstituted aryl), and _-C 1 -C ₄ alkylene - Or independently selected from (substituted or unsubstituted heteroaryl), or
Two R ⁹ groups attached to the same N atom are obtained together with the N atom to which they are attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl , Substituted or unsubstituted C 2 -C 10 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkenene (substituted or unsubstituted C 3 -C 10 cycloalkyl), -C ₁ -C ₄ alkylene -(Substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkenene (substituted or unsubstituted aryl), or -C ₂ -C ₄ alkylene- (substituted or unsubstituted heteroaryl) Yes,
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments, ring A is selected from pyrrolyl, thiazolyl, oxazolyl, isoxazodyl, oxadiazolyl, imidazolyl, pyrazolyl, isocyanzolyl, triazolyl and tetrazolyl.

  In some embodiments,

Is

Is selected from, where, X is O, S or NR ^A. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NR ^A.

In some embodiments, both R ¹ together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl; both R ² are It is obtained together with the carbon that is attached to form C (= S); both R ³ are obtained together with the carbon that is attached to form -C (= O).

  In some embodiments, the compounds described herein have the structure of Formula (III):

Here, p is 0, 1, 2 or 3.

In some embodiments, R ^A is H, halogen, -CN, -NO ₂ , -OH, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -S (= O) _{2, respectively.} N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or non Substituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C 6 alkoxy, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic It is independently selected from heteroaryl.

In some embodiments, R ⁴ is H, halogen, -CN, -NO ₂ and -OH, respectively. From substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy and substituted or unsubstituted C ₁ -C ₆ alkoxy R ⁵ is independently selected; substituted or unsubstituted C ₂ -C ₁₀ alkyl substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkoxy, substituted or unsubstituted L-substituted C ₂ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₂ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterofluoroalkyl or -L ¹ -L ² -R ⁶ ; L ¹ does not exist, -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O)-, -C (= O) NH -,-NHC (= ) -, - NHS (= O ) 2 -, or _{-S (= O) 2 NH-;} L 2 is a substituted or unsubstituted _C 1 -C ₆ alkylene, substituted or unsubstituted _C 1 -C ₆ fluoro Alkylene or substituted or unsubstituted C ₁ -C ₆ heteroalkylene; R ⁶ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , _{^{-S (= O) 2 R 10}} , -S (= O) 2 N (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C ( = O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted Unsubstituted bicyclic heteroaryl, substituted or unsubstituted phenyl, or substituted or substituted It is unsubstituted naphthyl.

In some embodiments, each R ⁴ is H, halogen, -CN, -NO ₂ , -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl , Independently selected from substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy and substituted or unsubstituted C ₁ -C ₆ alkoxy; R ⁵ is H, halogen, -CN, -NO ₂ , -OH , -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -S (= O) N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , _{^{-CO 2 R 9, -N (R}} 9) 2, -C (= O) N (R 9) 2, -NR 11 C (= O) R 10, -NR 11 C (= O) OR 10, substituted or unsubstituted _C 1 _{-C 10} alkyl, substituted or unsubstituted _C 1 _{-C 10} fluorite Alkyl, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or _C 1 _{-C 10} fluoroalkoxy unsubstituted, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 _{-C 10} heteroaryl Alkyl or -L ¹ -L ² -R ⁶ ; L ¹ absent, -O-, or -C (= O) NH-;
L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , _{^{-S (= O) R 10,}} -S (= O) 2 R 10, -C (= O) R 10, -CO 2 R 9 and ^{-C (= O) N (R} 9) 2, substituted or unsubstituted Substituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or non It is substituted phenyl or substituted or unsubstituted naphthyl.

  In some embodiments, the compounds described herein have the structure of Formula (III):

Wherein ring A is monocyclic heteroaryl, bicyclic heteroaryl or naphthyl;
m is 1 or 2;
Each R ^A is independently H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , _{^{-N (R 11) S (=}} O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R ⁹ , -N (R ⁹ ) ₂ , -C (OO) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C _1- C ₆ alkoxy or C ₁ -C ₆ heteroalkyl;
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
Each ^{R 4} is, independently, H, _{^{halogen, -CN, -NO 2, -OH,}} -OR 9, -SR 9 -, - S (= O) R 10, -S (= O) 2 R 10 _{^{, -N (R 11) S (}} = O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO ₂ R ⁹ , -OCO ₂ R ¹⁰ , -N (R ⁹ ) ₂ , -C (= O) N (R ⁹ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ heteroalkyl;
R ⁵ is substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl and substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, -L ¹ -L ^2- R ⁶ or-L ^1- R ⁷ ;
L ¹ does not exist, or -O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -C (= O), -C (= O) NH- , -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O -, - OC (= O ) NH -, - NHS (= O) 2 -, or -S _{(= O)} is 2 NH-; ^{L 2} is _C 1 -C _{6 alkylene,} C 1 -C ₆ fluoro Alkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O ) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ^10, _-CO 2 ^R 9, _{^{OCO 2 R 10, -N (R}} 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl and C ₁ -C ₆ heteroalkyl substituted or Unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl, substituted or unsubstituted Unsubstituted phenyl or substituted or unsubstituted naphthyl; R ⁷ is substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted Single ring Phenyl, or substituted or unsubstituted monocyclic heteroaryl; each ^{R 9} is, _H, C 1 -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 1 -C ₆ fluoro Alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted aryl ), and _-C 1 -C ₄ alkylene - (substituted or independently from unsubstituted heteroaryl) is selected, or, to the same N atom The two R ⁹ groups which together, they are bound to form a C ₂ -C ₁₀ heterocycloalkyl substituted or unsubstituted, obtained together with the N atom, R ¹⁰ is a substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C _1- C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), _- C 1 -C ₄ Arukeren - (substituted or unsubstituted aryl), or _-C 2 -C Alkylene - a (substituted or unsubstituted ^{heteroaryl), R 11} is H or _C 1 -C ₄ alkyl, p is 0, 1, 2 or 3.

In some embodiments, R ⁵ is substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl and substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic And L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ , L ^{1 is} absent, -O- or -C (= O) NH-, and L ² is C _1-. C ₄ fluoroalkyl, R ⁶ is C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl Or substituted or unsubstituted phenyl, and R ⁷ is C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic Fen Or a substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl.

  In some embodiments, provided herein is a compound of Formula (IV):

Alternatively, pharmaceutically acceptable salts, solvates, metabolites, N-oxides or prodrugs thereof are described, wherein
R ¹ is independently selected from H, -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, respectively And
Or, both R ¹ are incorporated together with the carbon linked to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl. , X ¹ is CR ^A or N; X ² is CR ^A or N; X ³ is CRA or N, and at least ^{two of} X ¹ , X ² and X ³ are CR ^A. R ^A represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N, respectively. (R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ^{9 _{, -N (R 9) 2,}} -C (= O) N (R 9) 2, substituted or unsubstituted C -C ₆ alkyl, substituted or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 1 -C ₆ cycloalkyl, or unsubstituted _C 1 -C ₆ heteroalkyl, substituted or unsubstituted _{C 2} -C ₆ cycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
Ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl;
n is 0, 1 or 2;
R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₆ alkoxy or substituted or unsubstituted C ₁ -C ₆ heteroalkyl;
R ⁵ is halogen, —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —N (R ¹¹ ) S _{^{(= O) 2 R 10,}} -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -OCO 2 R _{^{10, -N (R 9),}} - OC (= O) N (R 9) 2, -NR 11 C (= O) N (R 9) 2, -NR 11 C (= O) R 10, -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted substituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 _{-C 10} heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl monocyclic or ^-L 1 ^-L 2 -R ⁶ L ¹ does not exist, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O)-, -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O -, - OC ( = O) NH -, - NHS (= O) 2 -, or -S (= _{O) 2} - and is, ^{L 2} is a substituted or unsubstituted _C 1 -C ₆ alkylene R ⁶ is substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or substituted or unsubstituted C ₁ -C ₆ heteroalkylene; _{^{, -CN, -NO 2, -OH,}} -OR 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -N (R 11) S (= O) 2 R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , —OCO ₂ R ¹⁰ , —N ( R ⁹ ) ₂ , —C (= O) N (R ⁹ ) ₂ , —OC (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted Monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl or substituted or unsubstituted aryl;
R ⁹ represents H, substituted or unsubstituted C ₁ -C ₄ alkylene, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl or _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocyclo Alkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl) and -C ₁ -C ₄ alkylene- (substituted or unsubstituted Selected independently from
Two R ⁹ groups linked to the same N atom are obtained together with the linked N atom to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- ( Substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), —C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), —C ₁ -C ₄ alkylene- (substituted or non Substituted aryl) or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl);
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments,

Is

And
Here, X ¹ is CR ^A or N, X ² is CR ^A or N, X ³ is CR ^A or N, and at least ^{two of} X ¹ , X ² and X ³ are CR ^A I defined that there is.

  In some embodiments,

Is

Where m is 0, 1, 2, 3 or 4.

  In some embodiments,

Is

It is.

  In some embodiments, the compound of formula (IV) has the structure of formula (V):

have.

In some embodiments, ring B is phenyl and R ⁴ is H, halogen, -CN, -OH, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ Fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy or substituted or unsubstituted C ₁ -C ₆ alkoxy,
R ⁵ represents a halogen, —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (OO) R ¹⁰ , —CO ₂ R ⁹ , —N (R ⁹ ) ₂ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ — C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or -L ¹ -L ² -R ⁶ , , or not ^{L 1} exist, - _{-, - S -, - S} (O) -, - S (O) 2 -, - NH -, - C (= O) -, - C (= O) NH-, or -S (= _{O) 2} NH-, L ² is substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted C ₁ -C ₆ fluoroalkylene, substituted or unsubstituted C ₁ -C ₆ heteroalkylene, R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R) ⁹ ) ₂ , -CO ₂ R ⁹ and -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, Substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl or substituted or unsubstituted An aryl of conversion.

In some embodiments, R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , respectively. —C (= O) R ¹⁰ , —CO ₂ R ⁹ and —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ It is independently selected from fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy or substituted or unsubstituted C ₁ -C ₆ alkoxy.

  In some embodiments, a compound of Formula (I), (Ia), (II), (IV) or (V) has a structure of Formula (VI):

Have

  In some embodiments, a compound of Formula (I), (Ia), (II), (IV) or (V) has a structure of Formula (VI):

Have, where
One R ^A is —CN, —NO ₂ , —S (= O) ₂ R 10, —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ Or -C (= O) N (R ⁹ ) ₂ and the other R ^A is H, halogen, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoro Alkoxy and C ₁ -C ₆ alkoxy,
Both R ¹ are taken together with the carbon atom which is attached to form a C ₃ -C ₆ cycloalkyl,
Alternatively, each R ¹ is independently C ₁ -C ₄ alkyl,
R ⁴ is H, halogen, —OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy or C ₁ -C ₄ alkoxy.

In some embodiments, R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ; L ^{1 is} absent, -O-, or -C (= O) NH- L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ^{9 _{, -S (= O) R 10}} , -S (= O) 2 R 10, -C (= O) R 10, -CO 2 R 9 and ^{-C (= O) N (R} 9) 2, substituted or Unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted phenyl; R ⁷ is a substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl Or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, one R ^A is -CN and the other R ^A is H, F, Cl, -OH, -CH ₃ , -CF ₃ , -OCF ₃ , -OCH ₃ , or- OCH ₂ CH ₃ In some embodiments, one R ^A is -CN and the other R ^A is -CH ₃ or -CF ₃ .

In some embodiments, both R ¹ are taken together with the carbon atom that is attached to form cyclobutyl, or R ¹ is each —CH ₃ .

In some embodiments, R ⁵ is -L ¹ -L ² -R ⁶ or -L ¹ -R ⁷ ; L ^{1 is} absent, -O-, or -C (= O) NH- L ² is C ₁ -C ₆ alkylene, R 6 is substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted phenyl, R 2 is ⁷ is a substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl or substituted or unsubstituted heteroaryl or substituted or unsubstituted phenyl. In some embodiments, R ⁵ is -L ¹ -L ² -R ⁶ , L ¹ is -C (= O) NH, and L ² is C ₁ -C ₄ alkylene, substituted or unsubstituted N-containing 5- or 6-membered C ₂ -C ₆ heterocycloalkyl, and in some embodiments, R ⁵ is -L ¹ -R ⁷ and L ^{1 is} absent or -O- Or -C (= O) NH-, wherein R ⁷ is a substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, or a substituted or unsubstituted monocyclic 5- or 6-membered monocyclic ring Ring C ₂ -C ₆ heterocycloalkyl or or substituted or unsubstituted monocyclic 5- or 6-membered heteroaryl.

In some embodiments, one R ^A is —CN, —NO ₂ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ and —C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl, and the other R ^A is H , Halogen, -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy or substituted or unsubstituted C ₁ -C ₆ alkoxy, R ⁴ is H, halogen, -CN and -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ Furuoroarukokishima A substituted or unsubstituted _C 1 -C ₆ alkoxy, ^{R 5} is ^{_{halogen, -CN, -NO 2, -OH,}} -OR 9, -S (= O) 2 R 10, -S (= O ) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted Or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, Substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or -L ¹ -L ² -R ⁶ , L ¹ absent or not ,-O , Or -C (= O) a NH-, ^{L 2} is a substituted or unsubstituted _C 1 -C ₆ alkylene, substituted or unsubstituted _C 1 -C ₆ fluoroalkylene or substituted or unsubstituted _{C 1} - C ₆ heteroalkylene, wherein R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —CO ₂ R ⁹ and —C (= O) N (R ⁹ ) 2, substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted phenyl is there.

  In some embodiments, provided herein is a compound of Formula (VII):

Alternatively, pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs thereof are described, wherein
R ¹ is independently selected from H, -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, respectively ,
Or both R ¹ are obtained together with the carbon atoms which are bound to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or C ₂ -C ₁₀ heteroalkyl,
R ^A is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R _{^{11) S (= O) 2}} R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, - N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkoxy, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted phenyl group or unsubstituted phenyl or substituted or unsubstituted heteroaryl,
Ring B is a 5-membered heteroaryl, bicyclic heteroaryl or naphthyl,
n is 0, 1 or 2;
R ⁴ is H, halogen, -CN, -NO ₂ and -OH substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _1- C ₆ fluoroalkoxy or substituted or unsubstituted C 1 -C ₆ alkoxy,
R ⁵ represents H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹⁾ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -C (= O) R ¹⁰ , -OC (= O) R ¹⁰ , -CO ₂ R ⁹ , -OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —C (OO) N (R ⁹ ) ₂ , —OC (= O) N (R ₉ ) ₂ , —NR ¹¹ C (= O) N (R ⁹ ) ₂ ) —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₂ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₁₀ fluoroalkyl, substituted or unsubstituted _C 1 _{-C 10} fluoroalkoxy, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _C 1 -C ₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, heteroaryl monocyclic substituted or unsubstituted, or -L ¹ -L ² -R ⁶ and L ¹ does not exist, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O ), —C ((O) NH—, —NHC ((O) —, —NHC (= O) O—, —NHC (= O) NH—, —C (= O) O—, —OC ( = O)-, -OC (= O) O-, -OC (= O) NH-, -NHS (= O) ₂ or -S (= O) ₂ NH-, and L ² is substituted or non- _C 1 -C ₆ alkylene substituted, substituted or unsubstituted _C 1 -C ₆ fluoroalkylene or substituted or unsubstituted _C 1 -C A heteroalkylene, ^{R 6} is _{^{halogen, -CN, -NO 2, -OH,}} -OR 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , —S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ^{9 _{, -OCO 2 R 10, -N (}} R 9) 2, -C (= O) N (R 9) 2, -OC (= O) N (R 9) 2, -NR 11 C (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl or substituted Is unsubstituted aryl;
R ⁹ represents H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heteroalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted substituted aryl) and _-C 1 -C ₄ alkylene - (substituted or unsubstituted heteroaryl), or two ^{R 9} groups which are bonded to the same atom,換又is obtained together with the N atom attached to form a C ₂ -C ₁₀ heterocycloalkyl unsubstituted,
R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C _3- C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl), or _-C 1 -C ₄ alkylene - (substituted or unsubstituted Aryl) or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl),
R ¹¹ is H or C ₁ -C ₄ alkyl.

  In some embodiments, provided herein is a compound of Formula (VIII):

Alternatively, pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs thereof are described, wherein R ¹ is H, -OH substituted or unsubstituted C ₁ -C _{6 respectively} R ¹ independently selected from alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, or both R ¹ are substituted or unsubstituted C _3- C ₆ cycloalkyl or carbon atoms attached to form a substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, taken together with X being O or S, R ^A respectively H, _{^{halogen, -CN, -NO 2, -OH,}} -OR 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -N (R 11) S (= O) ₂ R ¹⁰ , -S (= O) ₂ ^{N (R 9) 2, -C} (= O) R 10, -OC (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) N (R 9) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl , Independently selected from substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl, ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl, n is 0, 1 or 2 and R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= _O) 2 ^{R 10,} substituted or unsubstituted _C 1 -C ₆ alkyl, location Or unsubstituted _C 1 -C ₆ fluoroalkyl, substituted or _C 1 -C ₆ fluoroalkoxy unsubstituted, substituted or unsubstituted _C 1 -C ₆ alkoxy, or substituted or unsubstituted _C 1 -C ₆ heteroalkyl, And R ⁵ is halogen, —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , —N (R _{^{11) S (= O) 2}} R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R 9, - OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —C (= O) N (R ₉ ) ₂ , —OC (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) N (R ⁹ ) ₂ , -NR ¹¹ C (= O) R ¹⁰ , -NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C _1- C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C _1- C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl Or-L ^1- L ^2- R ⁶ and L ¹ does not exist,-O-,-S-,-S (O)-,-S (O) ₂ -,-NH-,-C (= O), -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC ( = O)-, -OC (= O) O-, -OC (= O) NH ( ^{4) -, - SR 3 -} , - S (= O) 2 - and -S ^{(= O)} is 2 NH-, ^{L 2} is a substituted or unsubstituted _C 1 -C ₆ alkylene, substituted or unsubstituted a of _C 1 -C ₆ fluoroalkylene or substituted or unsubstituted _C 1 -C ₆ ^{heteroalkylene,} R ₆ ^{is, -CN, -NO 2, -OH,} -OR 9, -SR 9, -S (= _{^{O) R 10, -S (=}} O) 2 R 10, -N (R 11) S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , —OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —C (= O) N (R ⁹ ) ₂ , —OC (= O) ) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , Substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl Or substituted or unsubstituted aryl, wherein R ⁹ is H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C _1- C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ a Killen - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl) and _-C 1 -C ₄ alkylene - (substituted or unsubstituted aryl) and _-C 1 -C ₄ alkylene - (substituted or unsubstituted heteroaryl Two R ⁹ groups which are aryl) or which are attached to the same N atom are taken together with the N atom which is linked to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl R ¹⁰ is substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or Hi置Heteroaryl, _-C 1 -C ₄ alkylene - (substituted or unsubstituted _C 3 _{-C 10} cycloalkyl), _- C 1 -C ₄ alkylene - (substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl) , -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl) or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl), R ¹¹ is H or C ₁ -C ₄ alkyl is there.

In some embodiments, X is S, ring B is phenyl and R ⁴ is H, halogen, -CN, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , which is composed of C ₁ -C ₆ fluoroalkoxy and C ₁ -C ₆ alkoxy. _{^{, -S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkyl, substituted or unsubstituted C ₁ -C ₁₀ fluoroalkoxy, substituted or unsubstituted _C 1 _{-C 10} alkoxy, substituted or unsubstituted _{C 1} - ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, heteroaryl monocyclic substituted or unsubstituted, or -L ¹ -L ² -R ⁶ and L ¹ does not exist, -O-, -S-, -S (O)-, -S (O) _2- , -NH-, -C (= O ), —C (又 は O) NH—, or —S (OO) ₂ NH—, wherein L ² is a substituted or unsubstituted C ₁ -C ₆ alkylene, a substituted or unsubstituted C ₁ -C ₆ fluoroalkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene, R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , ^{_{-S (= O) 2 R 10}} , -S (= O) 2 N (R 9) , _-CO 2 ^{R 9} and ^{-C (= O) N (R} 9) 2, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted It is substituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl or substituted or unsubstituted aryl.

In some embodiments, R ^A is H, halogen, -CN, -NO ₂ , -OH, -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , respectively. ^{-C (= O) R 10,} -CO 2 R 9 and _{^{-C (= O) N (R}} 9) 2, is selected C 1 -C ₆ alkyl and _C 1 -C ₆ independently alkoxy.

  In some embodiments, provided herein is a compound of Formula (VIIIa):

Alternatively, pharmaceutically acceptable salts or N-oxides thereof are described, and both R ¹ are substituted or unsubstituted C ₃ -C ₆ cycloalkyl or substituted or unsubstituted C ₂ -C ₆ hetero Taken together with the carbon atoms attached to form a cycloalkyl, or each R ₁ is H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C _1- C ₆ heteroalkyl, X is O or S, R ^A is C ₁ -C ₆ alkyl, ring B is phenyl, naphthyl, monocyclic heteroaryl or bicyclic heteroaryl And n is 0, 1 or 2; R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ ,- S (= O) ₂ R ¹⁰ , C ₁ -C _{6 Alkyl,} a C 1 -C _{6 fluoroalkyl,} C 1 -C _{6 fluoroalkoxy,} C 1 -C ₆ alkoxy or _C 1 -C ₆ heteroalkyl, ^{R 5} is halogen, _-CN, -NO 2, -OH , -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -N (R ¹¹ ) S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —OC (= O) R ¹⁰ , —CO ₂ R ⁹ , —OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —C (= O) ) N (R ⁹ ) ₂ , —OC (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ^{11 _{C (= O) OR 10,}} C 1 -C 10 _alkyl, C 1 _{-C 10 fluoroalkyl,} C 1 _{-C 10} fluoroalkoxy C ₁ -C ₁₀ alkoxy and _C 1 _{-C 10} heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} heterocycloalkyl, substituted or unsubstituted phenyl, substituted Or unsubstituted monocyclic heteroaryl or -L ¹ -L ² -R ⁶ in which L ^{1 is} absent, or -O-, -S-, -S (O)-, -S (O) ₂ -, -NH-, -C (= O), -C (= O) NH-, -NHC (= O)-, -NHC (= O) O-, -NHC (= O) NH-, -C (= O) O-, -OC (= O)-, -OC (= O) O-, -OC (= O) NH (R ⁴ )-, -SR ^3- , -S (= O) _2- and -S _{(= O)} is 2 NH-, ^{L 2} is _C 1 -C _{6 alkylene,} C 1 -C ₆ fluoroalkylene or C -C ₆ heteroalkylene in ^Aari, R ₆ ^{is, -CN, -NO 2, -OH,} -OR 9, -SR 9, -S (= O) R 10, -S (= O) 2 R 10, _{^{-N (R 11) S (=}} O) 2 R 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -OC (= O) R 10, -CO 2 R ⁹ , —OCO ₂ R ¹⁰ , —N (R ⁹ ) ₂ , —C (= O) N (R ⁹ ) ₂ , —OC (= O) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) ) N (R ⁹ ) ₂ , —NR ¹¹ C (= O) R ¹⁰ , —NR ¹¹ C (= O) OR ¹⁰ , substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl, substituted or unsubstituted bicyclic heteroaryl or substituted or Unsubstituted an aryl, each _{^{R 9, H, C 1 -C}} 6 _alkyl, C 1 -C _{6 heteroalkyl,} C 1 -C ₆ fluoroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, Substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl or -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl) and -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl) or two R ⁹ groups bonded to the same N atom are換又is obtained together with the N atom attached to form a _C 2 _{-C 10} heterocycloalkyl ^{unsubstituted, R 10} _is, C 1 -C _{6 alkyl,} C 1 -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted Or unsubstituted heteroaryl, -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted C ₂ -C ₁₀ hetero Cycloalkyl), -C ₁ -C ₄ alkylene- (substituted or unsubstituted aryl), or -C ₁ -C ₄ alkylene- (substituted or unsubstituted heteroaryl And R ¹¹ is H or C ₁ -C ₄ alkyl.

In some embodiments, X is CR ⁷ and B is phenyl; R ⁴ is H, halogen, -CN, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl , C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy, and R ⁵ is halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ^{10 _{, -S (= O) 2 R}} 10, -S (= O) 2 N (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) N (R ⁹ ) ₂ , C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C ₁₀ alkoxy and C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or _C 2 _{-C 10} heterocycloalkyl substituted, substituted or unsubstituted phenyl, heteroaryl or ^-L 1 ^-L 2 -R ⁶ monocyclic substituted or unsubstituted; ^{L 1} absent, -O _{-, - S -, - S} (O) -, - S (O) 2 -, - NH -, - C (= O) -, - C (= O) NH-, or -S (= _{O) 2} L ² is C ₁ -C ₆ alkylene, C ₁ -C ₆ fluoroalkylene or C ₁ -C ₆ heteroalkylene; R ⁶ is —CN, —NO ₂ , —OH, —OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , -S (= O) ₂ N (R ⁹ ) ₂ , -CO ₂ R ⁹ and -C (= O) N ^(R _{9) 2,} substituted or unsubstituted _C 3 _{-C 10} cycloalkyl, substituted or unsubstituted _C 2 _{-C 10} hetero Cycloalkyl, substituted or unsubstituted monocyclic heteroaryl, a substituted or unsubstituted bicyclic heteroaryl, or substituted or unsubstituted aryl.

In some embodiments, R ^A is C ₁ -C ₆ alkyl, and both R ¹ are taken together with the carbon atom that is attached to form a C ₃ -C ₆ cycloalkyl Or each R ¹ is independently C ₁ -C ₄ alkyl.

  In some embodiments, the compound of formula (VIII) has the structure of formula (IX)

have.

In some embodiments, each R ^A is independently selected from H, halogen, -OH, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy.

  In some embodiments, the compound of Formula (VIIIa) has the structure of Formula (IXa)

have.

Each R ⁹ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, and substituted or unsubstituted monocyclic heteroaryl or independently attached to the same N atom The two R ⁹ groups are obtained together with the N atom which is attached to form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.
R ¹⁰ is C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ Heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, ^{R 5} is ^{halogen, -CN, -OH, -OR 9,} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ , —N (R ⁹ ) ₂ , —C (= O) NH (R ⁹ ), C ₁ -C ₁₀ Alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or -L ¹ -L ² -R ⁶ ; L ¹ absent or -O- , -S-, -S (O)-, -S (O) _2- , -NH- , -C (= O)-, -C (= O) NH-, or -S (= O) ₂ NH-; L ² is C ₁ -C ₄ fluoroalkyl, R ⁶ is- _{^{CN, -OH, -OR 9, -SR}} 9, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) 2 N (R 9) 2, -CO 2 R ⁹ and -C (= O) N (R ⁹ ) ₂ , substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic Or a substituted or unsubstituted phenyl.

In some embodiments, R ^A is —CH ₃ and both R ¹ is taken together with the carbon atom that is attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Or R ¹ is each —CH ₃ ; R ⁵ is halogen, —CN, —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ^{10 _{, -S (= O) 2 N}} (R 9) 2, -C (= O) R 10, -CO 2 R 9, -N (R 9) 2, -C (= O) NH (R 9), C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ fluoroalkyl, C ₁ -C ₁₀ fluoroalkoxy, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl , substituted or unsubstituted C -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, heteroaryl or ^-L 1 ^-L 2 -R ⁶ monocyclic substituted or unsubstituted; ^{L 1} absent, -O -, - S —, —S (O) —, —S (O) ₂ —, —NH—, —C (= O) —, —C (= O) NH— or —S (= O) ₂ NH— L ² is C ₁ -C ₄ fluoroalkyl and R ⁶ is substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted monocyclic heteroaryl or substituted or unsubstituted Is phenyl.

  In some embodiments, the compound of Formula (VIII) or Formula (VIIIa) has the following structure:

Have.

In some embodiments, R ^A is H, halogen, -OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy. In some embodiments, R ^A is C ₁ -C ₄ alkylene. In some embodiments, R ^A is -CH ₃ .

In some embodiments, R ⁴ is H, halogen, -CN, -NO ₂ , -OH, -OR ⁹ , -SR ⁹ , -S (= O) R ¹⁰ , -S (= O) ₂ R ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy or C ₁ -C ₆ heteroalkyl. In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is F.

In some embodiments, ^{R 5} is ^{halogen, -CN, -OH, -OR 9,} -SR 9, -S (= O) R 10, -S (= O) 2 R 10, -S (= O) ₂ N (R ⁹ ) ₂ , —C (= O) R ¹⁰ , —CO ₂ R ⁹ and —C (= O) N (R ⁹ ) ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ Fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ alkoxy. In some embodiments, R ⁵ is —CO ₂ R ⁹ or —C (= O) N (R ⁹ ). In some embodiments, R ⁵ is —CO ₂ H and —C (= O) NH ₂ or —C (= O) NH (CH ₃ ).

  In some embodiments herein, a compound of Formula (X):

Or pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs thereof. Here, each R ¹ is independently selected from H and —CH ₃ , or both R ¹ are taken together with the carbon atoms that are linked to form cyclobutyl. Wherein X is O or S; X ¹ is CH or N; R ^A is -CN or -C (= O) NH ₂ ; R ⁵ is -CO ₂ H, or -C (= O) NH ₂

  In some embodiments, provided herein is Formula (X):

Or a pharmaceutically acceptable salt, solvate, N-oxide, metabolite or prodrug thereof. Wherein each R ¹ is independently selected from H or —CH ₃ , or both R ¹ are taken together with the carbon atom to which it is attached to form cyclobutyl.
Wherein X is O; X ¹ is CH or N; R ^A is -CN or -C (= O) NH ₂ ; R ⁵ is -CO ₂ H and -C (= O) NH ₂ or -C (= O) NH (CH ₃ ).

  In some embodiments herein, a compound of Formula (X):

Or pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs thereof. Here, R ¹ is independently selected from H and —CH ₃ , or both R ¹ are taken together with the carbon atom to which it is attached to form cyclobutyl.
Wherein X is O or S; X ¹ is CH or N; R ^A is C (O) NH ₂ ,
R5 is -CO ₂ H and -C (= O) NH ₂ or -C (= O) NH (CH 3).

  Throughout the specification, groups and their substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

  In one aspect, the compounds described herein comprise the compounds in Table 1, or pharmaceutically acceptable salts thereof, or N-oxides thereof.

  The compounds disclosed herein are AR modulators. In certain embodiments, the compounds disclosed herein are AR inverse agonists, AR antagonists, AR degraders, AR transport modulators and / or AR DNA binding inhibitors. In some embodiments, the compounds disclosed herein are AR inverse agonists. In some embodiments, the compounds disclosed herein are AR antagonists. In some embodiments, the compounds disclosed herein are AR degraders. In some embodiments, the compounds disclosed herein are AR transport modulators. In some embodiments, the compounds disclosed herein are AR DNA binding inhibitors. The general properties of AR modulators for the treatment of prostate cancer include one or more of the aforementioned properties of AR modulators.

  In some embodiments, the compounds disclosed herein have the following characteristics: sufficient AR antagonist in prostate cancer cells, inverse AR agonist in prostate cancer cells, AR no agonist activity in prostate cancer cells, prostate cancer AR degrader activity in cells, non-antagonist or agonist or degrader activity in non-prostate cancer cells, inhibition of prostate cancer growth.

  In some embodiments, the compounds disclosed herein have the following characteristics: sufficient AR antagonist in prostate cancer cells, inverse AR agonist in prostate cancer cells, AR no agonist activity in prostate cancer cells, prostate cancer AR degrader activity in cells, and inhibition of prostate cancer growth.

  In some embodiments, the compounds disclosed herein have the following characteristics: sufficient AR antagonist in prostate cancer cells, inverse AR agonist in prostate cancer cells, AR no agonist activity in prostate cancer cells, prostate cancer Growth inhibition.

  In some embodiments, the compounds disclosed herein have the following characteristics: sufficient AR antagonist in prostate cancer cells, AR-free agonism activity in prostate cancer cells, inhibition of prostate cancer growth.

  In some embodiments, the compounds disclosed herein have the following characteristics: AR transport modulator, AR-free agonist activity in prostate cancer cells, Antagonist-free or agonist or decomposer activity in non-prostate cancer cells, prostate Inhibition of cancer growth.

  In some embodiments, the compounds disclosed herein have the following characteristics: AR transport modulator, AR-free agonist activity in prostate cancer cells, inhibition of prostate cancer growth.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa) or (X) compounds have minimal influence on minimal pro-convulsant activity and / or seizure threshold.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) or (X) show minimal modulation of GABAergic Cl channels (GABA-gated chloride channels).

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) or (X) show minimal binding to GABAergic Cl channels.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) or (X) have minimal antagonism of GABAergic Cl channels.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) or (X) are androgen receptor modulators with minimal interaction with GABAergic Cl channels.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) or (X) are androgen receptor modulators with minimal interaction with GABAergic Cl channels.

  GABA assays are known and are not limited, but are incorporated herein by reference. Ashok K. Mehta and Maharaj K. Ticku “Characterization of the Picrotoxin Site of GABA A Receptors” current Protocols in Pharmacology (2000) 1.18. 1-1.18.17; Copyright (c) 2000 by John Wiley & Sons, Inc. Also includes those described in

  In some embodiments, described herein is a method of treating cancer in a mammal comprising administering to the mammal a therapeutically effective amount of the compound, wherein the compound is a) androgen receptor Body inverse agonist; androgen receptor antagonist; androgen receptor degrader; androgen receptor transport modulator; androgen receptor DNA binding inhibitor; or a combination thereof; and b) minimal pre-convulsive activity and / or seizure Minimally affecting the threshold; showing minimal modulation of GABAergic Cl channels; showing minimal binding to GABAergic Cl channels: having minimal antagonism of GABAergic Cl channels With minimal interaction with GABAergic Cl channels; or their combination With the combined.

  In some embodiments, the compound has minimal interaction with a GABAergic channel. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is hormone refractory prostate cancer. In some embodiments, the compound is of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) , (IX), (IXa) or (X), or a pharmaceutically acceptable salt thereof or an N-oxide thereof.

  In some embodiments, methods of identifying androgen receptor modulators, including the following, are described herein: 1) Testing compounds for androgen receptor modulator activity in appropriate assays And 2) testing the same compound for activity on a GABAergic Cl channel in an appropriate in vitro or in vivo assay; where 1) shows activity, 2) any one of the following 1) Compounds are androgen receptor modulators: show minimal modulation of GABAergic Cl channels; show minimal binding to GABAergic Cl channels; minimal GABAergic Cl channels Have antagonism; or GABAergic Cl It has minimal interaction with the channel.

<Synthesis of Compound>
Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) described herein. The compounds of (IXa) and (X) are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein. Further, the solvents, temperatures, and other reaction conditions presented herein may vary.

  Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (IX) The starting materials used for the synthesis of compounds of X) are synthesized from or obtained from commercial sources such as, but not limited to, Sigma- Aldrich, Fluka, Acros Organics, Alfa Aesar, etc. The compounds described herein, and other related compounds with different substituents, are described in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992), Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed. , Vols. A and B (Plenum 2000, 2001) and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999), as described herein or as Otherwise it is synthesized using known techniques and materials. General methods for the preparation of compounds can be modified using appropriate reagents and conditions to introduce the various components found in the formulas as provided herein.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) and (X) are prepared as outlined in the following scheme.

In some embodiments, an amine of structure I is treated with a ketone or aldehyde R ¹ -C (= O) -R ¹ in a suitable solvent to provide a compound of structure II in the presence of NaCN. Ru. In some embodiments, the suitable solvent is acetic acid. In some embodiments, the reaction is performed at a temperature of 25 ° C to 80 ° C.

  In some embodiments, a compound of structure II is treated with thiophosgene and a compound of structure III in a suitable solvent and then treated with acid to provide thiohydantoins of structure IV. In some embodiments, the suitable solvent is dimethyl acetamide. In some embodiments, the reaction is heated to about 60.degree. In some embodiments, treatment with acid comprises treatment with hydrochloric acid. In some embodiments, treatment with acid includes treatment with HCl, MeOH at reflux for 2 hours.

  In some embodiments, the compounds disclosed herein are prepared as outlined in Scheme 2.

In some embodiments, a compound of structure V is produced to a compound of structure VI by reacting a compound of structure V with an electrophilic or nucleophile in the presence of a coupling agent. For example, in some embodiments, a compound of structure V is treated with a compound such as R ⁶ -L ² -OH in a suitable solvent to provide a compound of structure VI in the presence of DIAD and PPh ₃ Be done. In some embodiments, the solvent is tetrahydrofuran (tetrahydrofurn).

  In some embodiments, the compounds disclosed herein are prepared as outlined in Scheme 3.

Treatment of an ester of structure VII with a suitable base in a suitable solvent provides a carboxylic acid of structure VIII. In some embodiments, a suitable base is lithium hydroxide. In some embodiments, a suitable solvent is tetrahydrofuran. The carboxylic acid of structure VIII is then coupled with various agents to provide the compounds disclosed herein. In some embodiments, a carboxylic acid of structure VIII is treated with an amine R ⁶ -L ² -NH ₂ in the presence of a coupling reagent to provide an amide of structure IX. In some embodiments, a carboxylic acid of structure VIII is treated with an alcohol R ⁶ -L ² -OH in the presence of a coupling reagent to provide an ester as described herein. In some embodiments, the coupling reagent is EDC, DCC, BOP, HATU, etc. In some embodiments, the coupling reaction is carried out in the presence of a base in a solvent selected from dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane, dimethylformamide and the like. Suitable bases include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine and the like.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compounds of (IXa) and (X) are synthesized as outlined in the examples.

  Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

  A detailed description of techniques applicable to the formation of protecting groups or their removal can be found in the literature "Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999", and It is described in the document "Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994", which documents are incorporated herein by reference for such disclosure.

<Additional Form of Compound>
In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compounds of (IXa) and (X) have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomers, enantiomers, and epimeric forms as well as their suitable mixtures. The compounds and methods provided herein include all cis, trans, syn, anti, entogenes (E), and tozamen (Z) isomers, as well as suitable mixtures thereof. In certain embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) and (X) are prepared by reacting a racemic mixture of the compounds with an optically active resolving agent to form a set of diastereomeric compounds / salts, separating diastereomers, and optically By recovering the pure enantiomers, they are prepared as their individual stereoisomers. In some embodiments, separation of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by forming diastereomeric salts and performing separation by recrystallization or chromatography, or a combination thereof. See "Jean Jacques, Andre Collet, Samuel H. Wilen," Enantiomars, Racemates and Resolutions ", John Wiley And Sons, Inc, 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

  The methods and compositions described herein involve the use of crystalline forms (also known as polymorphs) as well as non-crystalline forms. In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts. Likewise, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein may exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

  In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, but not the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, prodrug design increases effective water solubility. Non-limiting examples of prodrugs are the compounds described herein. The compound is administered as an ester ("prodrug") to promote transport across cell membranes where water solubility impairs mobility, but then the compound is once carboxylic acid in cells where water solubility is beneficial. Acids are metabolically hydrolyzed to active entities. A further example of a prodrug may be a short chain peptide (polyamino acid) linked to an acid group, in which the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized to a biologically, pharmaceutically or therapeutically active form of a compound by one or more steps or processes.

  In one embodiment, the prodrug alters the metabolic stability or transport properties of the drug, masks side effects or toxicity, improves the flavor of the drug, or alters other characteristics or properties of the drug Can be designed as. Knowledge of in vivo pharmacodynamic processes and drug metabolism allows for the design of prodrugs of compounds once the pharmaceutically active compound is known. (Eg, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401, Rooseboom et al., Pharmacological Reviews, 56: 53-102, 2004; Aesop Cho, "Recent Advances in Oral Prodrug Discovery" . See T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, the Vol 14 of the A.C.S. Symposium Series); Annual Reports in Medicinal Chemistry, Vol 41, 395-407, 2006..

  Prodrug forms of the compounds described herein (wherein the prodrug is a compound of formula (I), (Ia), (II), (III), (IV), (IV), as described herein V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) are metabolized in vivo to produce the compounds within the scope of the claims include. In some cases, some of the compounds described herein may be alternative derivatives or prodrugs for the active compound.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa) and the site of the aromatic ring part of the compound of (X) are sensitive to various metabolic reactions. Therefore, incorporation of appropriate substituents of the aromatic ring structure reduces, minimizes or eliminates this metabolic pathway. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are, by way of example only, halogens, or alkyl groups.

  In another embodiment, the compounds described herein are isotopically (eg, using radioactive isotopes) or, but are not limited to, chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. It is labeled by other means, including use.

The compounds described herein include isotopically labeled compounds, wherein one or more atoms have an atomic mass or mass number that differs from the atomic mass or mass number normally found in nature. Are identical to those listed in the various formulas and structures shown herein except for the fact that they are substituted by Examples of isotopes that can be incorporated into the present compounds are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O , ¹⁷ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, etc. In one embodiment, isotopically labeled compounds described herein, for example, those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with an isotope such as deuterium provides certain therapeutic benefits resulting from metabolic stability, such as, for example, increased half-life in vivo, or decreased required dose.

  In further or additional embodiments, the compounds described herein are required to produce a metabolite that is then used to produce the desired effect, including the desired therapeutic effect, to an organism. It is metabolized by administration.

  "Pharmaceutically acceptable" as used herein refers to a substance such as a carrier or diluent that is relatively non-toxic without inhibiting the biological activity or properties of the compound, ie The substance may be administered to an individual without causing unwanted biological effects or without interacting in a deleterious manner with any component of the composition in which the substance is contained.

  The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organisms to be administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the pharmaceutically acceptable salt is a compound of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VII) It is obtained by reacting a compound of VIII), (VIIIa), (IX), (IXa) or (X) with an acid. Pharmaceutically acceptable salts are also of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) The compound of (IX), (IXa) or (X) is obtained by reacting with a base to form a salt.

  The compounds described herein may be formed and / or used as pharmaceutically acceptable salts. The type of pharmaceutically acceptable salt is, but not limited to, (1) a pharmaceutically acceptable inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid or, for example, acetic acid, Propionic acid, hexanoic acid, cyclopentyl propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3- (4- (4-) Hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-Methylbicyclo- [2.2.2] octa-2-ene-1-carboxylic acid, glucopeptonic acid, 4,4'-methylene (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, hydrocinnamic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, An acid addition salt formed by reacting an organic acid such as stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, etc. with the free base form of the compound; (2) present in parent compound Salts formed when the acidic protons are substituted by metal ions, such as alkali metal ions (eg, lithium, sodium, potassium), alkaline earth ions (eg, magnesium or calcium), or aluminum ions Including. In some cases, the compounds described herein are organic, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine, tris (hydroxymethyl) methylamine, etc. It can be in harmony with the base. In other cases, the compounds described herein can form salts with amino acids such as, but not limited to, arginine, lysine and the like. Acceptable inorganic bases used to form a salt with a compound that contains an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.

  It should be understood that reference to a pharmaceutically acceptable salt includes its solvent addition form or crystalline form, in particular a solvate or polymorph. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. . Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein may exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

  Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) and (IX) The compounds described herein, such as the compounds of X), may be in various forms, including but not limited to amorphous form, milled form and nanoparticulate form. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, melting points, density, hardness, crystalline form, optical properties, stability and solubility. Various factors such as recrystallization solvent, rate of crystallization, and storage temperature can cause the predominant single crystal form.

<Specific term>
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. As used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, NMR, HPCL, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used unless otherwise indicated. In this application, the use of "or" or "and" means "and / or" unless stated otherwise. Furthermore, as with the term "including", the use of other forms such as "include", "includes" and "included" is not limited. The section headings used herein are for organizational purposes only and are not to be constructed as limiting the described topics.

An "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group may be a saturated alkyl group or the alkyl group may be unsaturated alkyl. The alkyl moiety, whether saturated or unsaturated, may be branched or linear. An "alkyl" group has 1 to 10 carbon atoms (as appearing throughout this specification, numerical ranges such as "1 to 10" refer to each integer within the predetermined range, for example, By "1 to 10 carbon atoms" is meant that the alkyl group consists of one carbon atom, two carbon atoms, three carbon atoms, and at most 10 carbon atoms, but this definition also refers to (Including the presence of the term "alkyl" without the scope of In one embodiment, the alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl tertiary butyl, pentyl, neopentyl, hexyl, allyl, 2-enyl, 3-enyl and the like Including. In some embodiments, the alkyl is a C ₁ -C ₆ alkyl.

The term "alkylene" refers to a divalent alkyl radical. Any of the foregoing monovalent alkyl groups may be alkylene by extraction of the second hydrogen atom from the alkyl. In one aspect, alkylene is C1-C10 alkylene. In another aspect, alkylene is C ₁ -C ₆ alkylene.

Typical alkylene groups include, but are not limited _{to, -CH 2 -, - CH (} CH 3) -, - C (CH 3) 2 -, - CH 2 CH 2 -, - CH 2 CH (CH 3) -, _{-CH 2 C (CH 3) 2} -, - CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH 2 CH 2 CH 2 -, - CH 2 CH 2 CH ₂ CH ₂ CH ₂ CH ₂ - and the like.

  An "alkoxy" group refers to an (alkyl) O- group, wherein alkyl is as defined herein.

The term "alkylamine" refers to the group -N (alkyl) _x H _y , where x and y are selected from the groups x = 1, y = 1 and x = 2, y = 0.

  The term "aromatic" refers to a planar ring having a delocalized π electron system, including 4n + 2π electrons, where n is an integer. The aromatic ring may be formed of more than 5, 6, 7, 8, 9, 10 or 10 atoms. Aromatics are optionally substituted. The term "aromatic" includes both carbocyclic aryl ("aryl" such as phenyl) and heterocyclic aryl (or "heteroaryl" or "aromatic heterocycle") groups (such as pyridine). The term includes single or fused ring polycyclic (ie, rings which share adjacent pairs of carbon atoms) groups.

  The terms "carbocycle" or "carbocyclic compound" refer to a ring or ring system wherein all atoms forming the backbone of the ring are carbon atoms. The term thus distinguishes carbocycles from heterocycles which contain at least one atom whose ring backbone is different from carbon.

As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring is formed by more than 5, 6, 7, 8, 9, or 9 carbon atoms. The aryl group is optionally substituted. In one embodiment, the aryl is phenyl or naphthalenyl. In one embodiment, the aryl is phenyl. In one embodiment, the aryl is a C ₆ -C ₁₀ aryl. Depending on the structure, the aryl group may be monoradical or diradical (ie, an arylene group). Exemplary arylenes include, but are not limited to, phenyl-1,2-ene, phenyl-1,3-ene, and phenyl-1,4-ene.

  The term "cycloalkyl" refers to monocyclic or polycyclic aliphatic radicals, non-aromatic radicals, wherein each of the atoms forming the ring (i.e., a backbone atom) is a carbon atom. Cycloalkyls can be saturated or partially unsaturated. Cycloalkyls can be fused with an aromatic ring and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may be substituted or unsubstituted. Depending on the structure, the cycloalkyl group may be a monoradical or a diradical (ie, but not limited to, cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1, It may be a cycloalkylene group such as 1-diyl, cyclohexane-1,4-diyl, cycloheptane-1,1-diyl and the like). In one aspect, the cycloalkyl is a C3-C6 cycloalkyl.

  The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo or iodo.

The term "haloalkyl" denotes an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms. In one embodiment, haloalkyl is C ₁ -C ₆ haloalkyl.

The term "haloalkylene" denotes an alkylene group in which one or more hydrogen atoms are replaced by one or more halogen atoms. In one aspect, the haloalkylene is a C ₁ -C ₆ haloalkylene.

The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, fluoroalkyl is C ₁ -C ₆ fluoroalkyl.

The term "fluoroalkylene" refers to alkylene in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkylene is a C ₁ -C ₆ fluoroalkylene.

The term "heteroalkyl" is such that one or more of the skeletal atoms of the alkyl is selected from atoms other than carbon, such as oxygen, nitrogen (eg -NH-, -N (alkyl)-, sulfur, or combinations thereof. Alkyl group In one aspect, heteroalkyl is C ₁ -C ₆ heteroalkyl.

The term "heteroalkylene" refers to an alkylene group in which one or more of the alkyl backbone atoms is selected from an atom other than carbon, such as oxygen, nitrogen, sulfur, or combinations thereof. In one aspect, the heteroalkylene is a C ₁ -C ₆ heteroalkylene. A heteroalkylene comprising exemplary, but are not limited _{to, -OCH 2 -, - OCH (} CH 3) -, - OC (CH 3) 2 -, - OCH 2 CH 2 -, - OCH 2 CH 2 CH 2 -, - _{CH 2 O -, - CH (} CH 3) O -, - C (CH 3) 2 O -, - CH 2 CH 2 O -, - CH 2 OCH 2 -, - CH 2 OCH 2 CH 2 -, - CH ₂ CH ₂ OCH _2- , -SCH ₂ -,-SCH (CH ₃ )-, -SC (CH ₃ ) _2- , -SCH ₂ CH _2- , -CH ₂ S-, -CH (CH ₃ ) S- _{, -C (CH 3) 2 S} -, - CH 2 CH 2 S -, - CH 2 SCH 2 -, - CH 2 SCH 2 CH 2 -, - CH 2 CH 2 SCH 2 -, - SO 2 CH 2 - , -SO ₂ CH (CH ₃ )-, -SO ₂ C (CH ₃ ) ₂ -,- SO ₂ CH ₂ CH _2- , -CH ₂ SO _2- , -CH (CH ₃ ) SO _2- , -C (CH ₃ ) ₂ SO _2- , -CH ₂ CH ₂ SO _2- , -CH ₂ SO _{2 CH 2 -, - CH 2 SO} 2 CH 2 CH 2 -, - CH 2 CH 2 SO 2 CH 2 -, - NHCH 2 -, - NHCH (CH 3) -, NHC (CH 3) 2 -, - NHCH 2 _{CH 2 -, - CH 2 NH} -, - CH (CH 3) NH -, - C (CH 3) 2 NH -, - CH 2 CH 2 NH -, - CH 2 NHCH 2 -, - CH 2 NHCH 2 CH _{2 -, - CH 2 CH 2} NHCH 2 - , and the like.

  The terms "heterocycle" or "heterocyclic" refer to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (heteroalicyclic groups) which contain 1 to 4 heteroatoms in the ring. Wherein each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group is provided with the proviso that any ring does not contain two adjacent O or S atoms, It has up to 4 to 10 atoms in the ring system. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups are those in their ring system Must have at least 5 atoms. Heterocyclic groups include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridinyl. An example of a 4 membered heterocyclic group is azetidinyl. An example of a 5 membered heterocyclic group is thiazolyl. An example of a 6 membered heterocyclic group is pyridyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl Aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, diazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H Pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithioranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidini , Imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, a 3H- indolyl, and quinolizinyl. Examples of the aromatic heterocyclic group are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, Indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, frazanyl, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The aforementioned groups may be C-attached (or C-linked) or N-attached where they are possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Furthermore, groups derived from imidazole are imidazol-1-yl or imidazol-3-yl (both N-attached), or imidazol-2-yl, imidazol-4-yl, or imidazol- It may be 5-yl (all C-attached). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles may be substituted with one or two oxo (= O) moieties such as pyrrolidin-2-one.

  The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include the following moieties:

Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. In some embodiments, the heteroaryl comprises 0-3 N atoms in the ring. In some embodiments, the heteroaryl comprises 1 to 3 N atoms in the ring. In some embodiments, heteroaryl comprises 0 to 3 N atoms, 0 to 1 O atoms, and 0 to 1 S atoms in the ring. In some embodiments, heteroaryl is monocyclic or bicyclic heteroaryl. In some embodiments, the heteroaryl is a C ₁ -C ₉ heteroaryl. In some embodiments, monocyclic heteroaryl is a C ₁ -C ₅ heteroaryl. In some embodiments, monocyclic heteroaryl is 5 or 6 membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C ₆ -C ₉ heteroaryl. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (ie, a heteroarylene group).

  A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group that comprises at least one heteroatom selected from nitrogen, oxygen and sulfur. The radical may be fused to an aryl or heteroaryl. Illustrative examples of heterocycloalkyl groups, also represented as non-aromatic heterocycles, include:

In some embodiments, heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and indolinyl. In some embodiments, heterocycloalkyl is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl. The term "heteroalicyclic" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one embodiment, heterocycloalkyl is C ₂ -C ₁₀ heterocycloalkyl. In another embodiment, heterocycloalkyl is C ₄ -C ₁₀ heterocycloalkyl. In some embodiments, the heterocycloalkyl comprises 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl comprises 0 to 2 N atoms, 0 to 2 O atoms and 0 to 1 S atoms in the ring.

  The terms "bond" or "single bond" refer to a chemical bond between two atoms, or two parts, when the atoms linked by the bond are considered to be part of a larger substructure. In one embodiment, when the groups described herein are bonds, the referenced groups are not present, thereby allowing bonds to be formed among the remaining identified groups.

  The term "moiety" refers to a particular area or functional group of a molecule. Chemical moieties are often recognized as chemical moieties embedded or attached to a molecule.

  As used herein, the term "carboxylic acid bioisostere" refers to functional groups or moieties that exhibit similar physical, biological and / or chemical properties as the carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to:

The terms "optionally substituted" or "substituted" are alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, the reference group of which includes mono- and di-substituted amino groups and protected derivatives thereof Independently and independently selected from the formulas hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino Meaning that it may be substituted by one or more additional groups. As an example, the optional substituents are halide, -CN, are independently selected from -NO _2, and -LR, where each of the L, bond, -O -, - C (= O) -, -C (= O) O-, -S-, -S (= O)-, -S (= O) _2- , -NH-, -NHC (O)-, -C (= O) NH-, _{S (= O) 2 NH -} , - NHS (= O) 2, -OC (= O) NH -, - NHC (= O) O-, or - _(C 1 -C ₆ alkylene) - independently from the And each R is selected from H, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl. In some embodiments, optional substituents are _{halogen, -CN, -NH 2, -NH (} CH 3), - N (CH 3) 2, -OH, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl And is independently selected from heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are _{halogen, -CN, -NH 2, -NH (} CH 3), - N (CH 3) 2, -OH, -CO 2 H, -CO 2 alkyl, -C (= O) _{alkyl, -C (= O) NH 2} , -C (= O) NH ( alkyl), - C (= O) N ( _{alkyl) 2, -S (= O)} 2 NH 2, -S _{(= O)} 2 NH _{(alkyl), - S (= O)} 2 N ( _{alkyl) 2,} alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, -S- alkyl, or -S, ( OO) independently selected from ₂ alkyl. In some embodiments, optional substituents are _{halogen, -CN, -NH 2, -NH (} CH 3), - N (CH 3) 2, -OH, -CO 2 H, -CO 2 alkyl, -C (= O) _{alkyl, -C (= O) NH 2} , -C (= O) NH ( alkyl), - C (= O) N ( _{alkyl) 2,} alkyl, cycloalkyl, fluoroalkyl, heteroalkyl It is independently selected from alkoxy, and fluoroalkoxy. In some embodiments, optional substituents are _{halogen, -CN, -NH 2, -OH,} -NH (CH 3), - N (CH 3) 2, -CH 3, -CH 2 CH 3, _{-CF 3, -CH 2 CF 3,} -OCH 3, -OCH 2 CH 3, and are independently selected from -OCF _3. In some embodiments, a substituent is substituted with one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (excluding aromatic carbon atoms, acyclic or cyclic, saturated or unsaturated carbon atoms) include oxo (= O) .

  In certain embodiments, the compounds presented herein comprise one or more stereogenic centers, wherein each center is independently present in either the R or S configuration. The compounds presented herein include all diastereomers, enantiomers, and epimeric forms as well as their suitable mixtures. Stereoisomers are obtained, if desired, by methods such as stereoselective synthesis by chiral chromatography columns and / or separation of stereoisomers.

  The methods and formulations described herein are of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of (IX), (IXa) or (X) Also included is the use of active metabolites of these compounds having the same type of activity. In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In a specific embodiment, the compounds described herein are present in solvated form with a pharmaceutically acceptable solvent such as water, ethanol and the like. In other embodiments, the compounds described herein exist in unsolvated form.

  The term "acceptable" in reference to a formulation, composition or ingredient, as used herein, means not to adversely affect the general health of the subject being treated. .

  The term "modulate," as used herein, by way of example only, enhances the activity of the target, inhibits the activity of the target, limits the activity of the target, or extends the activity of the target In order to change the activity of the target, it means interacting with the target directly or indirectly.

  The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, agonists, half agonists, inverse agonists, antagonists, degraders, AR transport modulators, AR DNA binding inhibitors. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is an inverse agonist, an antagonist, a degrader, an AR transport modulator and / or a DNA binding inhibitor.

  The term "antagonist" as used herein refers to a small molecule drug that binds to the nuclear hormone receptor and subsequently reduces the transcriptional activity induced by the nuclear hormone receptor agonist.

  The term "agonist" as used herein refers to a small molecule drug that binds to the nuclear hormone receptor and subsequently increases nuclear hormone receptor transcriptional activity in the absence of a known agonist.

  The term "inverse agonist" as used herein binds to the nuclear hormone receptor and subsequently reduces the level of basal of nuclear hormone receptor transcriptional activity present in the absence of a known agonist, Refers to small molecule drugs.

  The term "degrader" as used herein refers to a small molecule drug that binds to the nuclear hormone receptor and subsequently lowers the protein level of said receptor in its steady state.

  The term "AR transport modulator" as used herein binds to a nuclear hormone receptor and subsequently alters the normal subcellular location of the receptor, thereby interfering with its function and signaling. , Refers to small molecule drugs.

  The term "DNA binding inhibitor" as used herein is a small molecule that binds to the nuclear hormone receptor and subsequently interferes with the DNA binding of the receptor, thereby interfering with its function and signal transduction. Refers to a drug.

  The term "AR-dependent", as used herein, refers to a disease or disorder that does not occur in the absence of the androgen receptor or not to the same extent.

  The term "AR-mediated", as used herein, refers to a disease or condition that can occur in the absence of an androgen receptor but can occur in the presence of an androgen receptor.

  "Selective" with respect to the androgen receptor means that the compound preferentially binds to the androgen receptor versus other nuclear receptors. In some embodiments, selective androgen receptor modulators bind preferentially to androgen receptors and exhibit little, if any, affinity for other nuclear receptors.

  The term "cancer" as used herein refers to abnormal growth of cells that grow in an uncontrolled manner and, in some cases, tend to metastasize (expand).

  The term "co-administration" or the like, as used herein, is meant to encompass the administration of a selected therapeutic agent to a single patient, either by the same or different routes of administration, or It is intended to include treatment regimens administered at the same or different times.

  The terms "effective amount" or "therapeutically effective amount", as used herein, is an amount sufficient to administer, to some extent, one or more symptoms of the disease or disorder being treated. Refers to a drug or compound. As a result, it may reduce and / or alleviate the signs, symptoms, or causes of the disease or result in any other desired change in the biological system. For example, an "effective amount" for therapeutic use is an amount of the composition comprising a compound disclosed herein which is required to clinically significantly reduce the symptoms of the disease. is there. An appropriate "effective" amount may be determined in any individual using techniques such as a dose escalation study.

  The terms "enhannce" or "enhancing" as used herein means increasing or prolonging the desired effect, either in potency or duration. . Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the effect of another therapeutic agent on the system, either in potency or duration. An "enhancing effective amount" as used herein refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

  The term "pharmaceutical combination", as used herein, results from the mixing or combination of more than one active ingredients, both fixed and non-fixed combinations of active ingredients Means the product. The term "fixed combination" refers to active ingredients such as Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), The compound of (VIIIa), (IX), (IXa) or (X) and the crosslinker (co-agent) are both administered simultaneously to the patient in the form of a single entity or dose. The term "non-fixed combination" refers to active ingredients such as Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIa) IX), the compound of (IXa) or (X) and the crosslinker are simultaneously, simultaneously or sequentially administered to the patient as separate entities without specific intervening time restrictions, where: Such administration results in effective levels of the two compounds in the patient's body. The latter term also applies to cocktail therapy, eg the administration of three or more active ingredients.

  The terms "kit" and "product" are used as synonyms.

  A "metabolite" of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized", as used herein, is a process in which certain substances are altered by an organism, including but not limited to hydrolysis reactions and enzyme catalysed reactions. Refers to the whole of Thus, enzymes can bring about certain structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase activates to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups It catalyzes the transfer of glucuronic acid molecules. The metabolites of the compounds disclosed herein may either be administered to the host and analysis of tissue samples from the host, or in vitro incubation of the compounds with hepatocytes and analysis of the resulting compounds Is optionally identified.

  The term "subject" or "patient" includes a mammal. Examples of mammals include, but are not limited to, any member of the mammalian class: human, non-human primates such as chimpanzees, and other apes and monkeys, such as cows, horses, sheep, goats, pigs etc. Includes laboratory animals, including domestic animals, domestic animals such as rabbits, dogs and cats, rodents such as rats, mice and guinea pigs, etc. In one embodiment, the mammal is a human.

  The terms "treat", "treating", or "treatment", as used herein, are either prophylactic and / or therapeutic, as a disease. Or alleviation, alleviation or amelioration of the disease, prevention of further symptoms, inhibition of the disease or disorder, eg, arrest of the progression of the disease or disorder, alleviation of the disease or disorder, regression of the disease or disorder, disease caused by the disease or disorder Including relieving the condition or stopping the symptoms of the disease or condition.

<Administration route>
Suitable administration routes include, but are not limited to, oral administration, intravenous administration, rectal administration, aerosol administration, parenteral administration, ocular administration, transpulmonary administration, transmucosal administration, transdermal administration, vaginal administration, and aural administration , Nasal administration, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal infusion as well as intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic and intranasal infusion.

  In certain embodiments, the compounds described herein are often in a depot or sustained release formulation, for example, in a local rather than systemic manner, via injection of the compound directly into an organ. It is administered. In specific embodiments, long-acting formulations are administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to the organ and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In still other embodiments, the compounds described herein are administered topically.

<Pharmaceutical composition / formulation>
In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in conventional manner with one or more pharmaceutically acceptable inert ingredients which facilitate the processing of the active compounds into pharmaceutically acceptable formulations. Proper formulation is dependent upon the route of administration chosen. A summary of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa .: Mack Publishing Company, 1995); , Remington's Pharmaceutical Sciences, Mack Publishing Co. Easton, Pennsylvania 1975; Liberman, H., et al. A. and Lachman, L. , Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N.A. Y. , 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosure.

  Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (IX) Provided herein are pharmaceutical compositions comprising a compound of X) and at least one pharmaceutically acceptable inactive ingredient. In some embodiments, the compounds described herein are of the formulas (I), (Ia), (II), (III), (IV), (IV), (V), (VI), as in combination therapy. , (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is administered as a pharmaceutical composition in which it is mixed with other active ingredients. In other embodiments, the pharmaceutical composition comprises other medical agents or drugs, carriers, adjuvants, preservatives, stabilizers, wetting agents or emulsifiers, dissolution enhancers, salts for adjusting the osmotic pressure, and / or Contains buffer. In yet other embodiments, the pharmaceutical composition comprises other therapeutically valuable substances.

  The pharmaceutical compositions, as used herein, are of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII) ), (VIIIa), (IX), (IXa) or (X) and a carrier, excipient, binder, filler, suspending agent, flavoring agent, sweetening agent, disintegrant, dispersion Agents, surfactants, lubricants, colorants, excipients, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoams, antioxidants, preservatives, or , A mixture with other chemical ingredients (ie, pharmaceutically acceptable inactive ingredients) such as one or more combinations thereof. Pharmaceutical compositions facilitate administration of the compound to a mammal.

  The therapeutically effective amount can vary widely, depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as a component of a mixture.

  The pharmaceutical formulations described herein are suitable routes of administration including, but not limited to, oral, parenteral (eg, intravenous, subcutaneous, intramuscular), nasal, buccal, topical, rectal or transdermal routes of administration. Can be administered to the subject. The pharmaceutical formulations described herein may be aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, sustained release formulations, fast dissolving formulations, tablets, capsules Including, but not limited to, pills, delayed release formulations, sustained release formulations, pulse release formulations, multiparticulate formulations, and immediate mixing and controlled release formulations.

  Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or , The pharmaceutical composition containing the compound of (X) is manufactured in a conventional manner, by way of example only, by means of conventional mixing, dissolving, granulating, dolasee making, wet grinding, emulsification, encapsulation, encapsulation or compression processes Be done.

  The pharmaceutical composition comprises at least one of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIa) Compounds of IX), (IXa) or (X) will be included as the active ingredient in free acid or free base form, or in pharmaceutically acceptable salt form. Furthermore, the methods and pharmaceutical compositions described herein also use N-oxides (where appropriate), crystalline forms, non-crystalline phases, as well as active metabolites of these compounds having the same type of activity. Including. In some embodiments, the compounds described herein are present in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

  The pharmaceutical compositions described herein are of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), ( VIIIa), (IX), (IXa) or (X), including, but not limited to, water-soluble oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, solid oral preparations Forms, controlled release formulations, fast dissolving formulations, foam formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulse release formulations, multiparticulate formulations, and mixed immediate release and It is formulated into any suitable dosage form, including controlled release formulations.

  Pharmaceutical preparations to be administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can comprise the active ingredient in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In some embodiments, push-fit capsules do not contain any other ingredients in addition to the capsule shell and the active ingredient. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.

  All formulations for oral administration are in dosages suitable for such administration.

  In one embodiment, the solid oral dosage forms are of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII) VIIIa), (IX), (IXa) or (X), prepared by mixing with one or more of the following: antioxidants, flavoring agents, and binders, suspending agents, disintegrants, Carrier materials such as fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

  In some embodiments, the solid dosage forms described herein comprise tablets (including suspension tablets, fast dissolving tablets, bite-disintegration tablets, fast disintegrating tablets, effervescent tablets or caplets) , Pills, powders, capsules, solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulse release dosage forms, multiparticulate dosage forms, beads, pellets, granule forms It is. In another embodiment, the pharmaceutical preparation is in powder form. In yet another embodiment, the pharmaceutical preparation is in the form of a tablet. In another embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) Pharmaceutical preparations of the compounds of (IXa) or (X) are in the form of capsules.

  In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, have the formulas (I), (Ia), (II), (III), (III), (IV), (V), (( VI) A particulate matter of a compound of (VII), (VIII), (VIIIa), (IX), (IXa) or (X), and one or more pharmaceutical excipients forming a large amount of mixed composition It is prepared by mixing with an agent. Bulk mixing is easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. In some embodiments, an individual unit dose comprises a coating of a membrane. These formulations are manufactured by conventional formulation techniques.

  Conventional formulation techniques include, for example, one or a combination of the following methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) Wet granulation, or (6) Fusion. Other methods are, for example, spray drying, pan coating, melt granulation, granulation, fluid bed spray drying or coating (eg wurster coating), tangential coating, top spraying, tableting, Including extrusion and the like.

  In some embodiments, the tablet will include a membrane surrounding the final compressed tablet. In some embodiments, the membrane coating is of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) Delayed release of the compounds of (IX), (IXa) or (X) can be provided. In other embodiments, the membrane coating assists in patient compliance (eg, Opadry® coating or sugar coating). The membrane coating comprising Opadry® is typically in the range of about 1 to about 3% by weight of the tablet.

  Capsules can be formulated, for example, by placing a large amount of the above-described formulation of the compound in the capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in soft gelatin capsules. In other embodiments, the formulation is placed in a standard gelatin capsule or in a non-gelatin capsule such as a capsule containing HPMC. In other embodiments, the formulation is placed in a dispersive capsule where the capsule is swallowed in its entirety or the capsule is opened and the contents are spread over the food prior to eating.

  In various embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) , (IXa) or (X) particles of the compound and one or more excipients are dry mixed and less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, about 50 minutes after oral administration Into a mass, such as a tablet, having sufficient hardness to provide a pharmaceutical composition that substantially degrades in less than about 55 minutes, or less than about 60 minutes, thereby releasing the formulation into the gastrointestinal fluid. It is compressed.

  In another embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) A powder comprising a compound of (IXa) or (X) is formulated to contain one or more pharmaceutical excipients and flavoring agents. Such powders may, for example, form formulas (I), (Ia), (II), (III), (IV), (V), (V), (VI), (VII) to form large amounts of mixed compositions. , (VIII), (VIIIa), (IX), (IXa) or (X), by mixing the compound with an optional pharmaceutical excipient. Additional embodiments also include suspending and / or wetting agents. This bulk mixing is uniformly subdivided into unit dose packaging or multi-dose packaging units.

  In yet another embodiment, a foam powder is also prepared. Effervescent salts are used to disperse the drug in water for oral administration.

  In some embodiments, the pharmaceutical solid oral dosage form is of the formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), ( Formula VIII) is formulated to provide controlled release of a compound of (VIIIa), (IX), (IXa) or (X). Controlled release may be of the formula (I), (Ia), (II), (III), (IV), (V), (V), (VI), (VII), from dosage forms incorporated according to the desired properties over time It refers to the release of compounds of (VIII), (VIIIa), (IX), (IXa) or (X). Controlled release properties include, for example, sustained release, extended release, pulsed release, and delayed release properties. In contrast to the immediate release composition, the controlled release composition enables the drug to be delivered to the subject for an extended period of time according to predetermined characteristics. Such a release rate allows a therapeutically effective level of the drug to be provided for an extended period of time, thereby providing a longer period of pharmacological response while at the same time side effects as compared to conventional rapid release dosage forms Is minimized. Such longer reaction times lead to a number of inherent advantages not achieved with the corresponding short acting, immediate release formulations.

  In some embodiments, the solid dosage forms described herein are enteric coated delayed release oral dosage forms, ie, utilizing enteric coatings to affect release in the small or large intestine. It is formulated as an oral dosage form of the described pharmaceutical composition. In one embodiment, the enteric coated dosage form comprises compressed or molded or extruded tablets / molds comprising granules, powders, pellets, beads or particles of the active ingredient and / or other composition elements Or uncoated), which are themselves coated or uncoated. In one embodiment, the enteric coated oral dosage form is a coated or non-coated Formula (I), (Ia), (II), (III), (III), (IV), (V), (VI) And (VII), (VIII), (VIIIa), (IX), (IXa) or (X), in the form of a capsule comprising pellets, beads or granules.

  The coating is applied using conventional coating techniques such as spraying or pan coating. The thickness of the coating should be sufficient to ensure that the oral dosage form remains intact before topical delivery reaches the desired site in the alimentary canal.

  In other embodiments, the formulations described herein are delivered using a pulsatile dosage form. The pulsatile dosage form can provide one or more immediate release pulses at predetermined points in time or at specific sites after the delay time has been controlled. Typical pulsatile dosage forms and methods for their preparation are described in U.S. Patent Nos. 5,011,692, 5,017,381, 5,229,135, 5,840,329 and 5 , 837, 284. In one embodiment, the pulsatile dosage form comprises at least two groups of particulate matter (ie, multiparticulates), each comprising a formulation as described herein. The first group of particulate matter, when taken up by a mammal, is represented by formulas (I), (Ia), (II), (III), (IV), (V), (V), (VI), (VII) And provides a substantially direct dose of a compound of (VIII), (VIIIa), (IX), (IXa) or (X). The first group of particulates may be uncoated or comprise coatings and / or sealants. In one embodiment, the second group of particulates comprises coated particulates. The coating on the second group of particulates provides a delay of about 2 hours to about 7 hours and is then ingested prior to the release of the second dose. Coatings suitable for pharmaceutical compositions are described herein or known in the art.

  In some embodiments, the pharmaceutical formulation is a compound of formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) Provided as particulate matter of the compound of (IX), (IXa) or (X) and at least one dispersing agent or suspending agent for oral administration to a subject. The formulations are powders and / or granules for suspension, and when mixed with water, a substantially homogeneous suspension is obtained.

  In one embodiment, liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. In the form of an aqueous suspension selected from Singh et al. , Encyclopedia of Pharmaceutical Technology, 2nd Ed. , Pp. See 754-757 (2002). Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (IX) In addition to the particulate matter of the compound of X), the liquid dosage form comprises the following additives: (a) a disintegrant; (b) a dispersing agent; (c) a wetting agent; (d) at least one One preservative, (e) a viscosity promoter, (f) at least one sweetener, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersion can further comprise a crystalline inhibitor.

  Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (IX) An oral formulation comprising a compound of X) is administered using various formulations known in the art. For example, such formulations include, but are not limited to, US Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosage forms described herein further comprise a bioerodible (hydrolyzable) polymeric carrier that also functions to adhere the oral dosage form to the buccal mucosa. For buccal or sublingual administration, the compositions may take the form of tablets, troches, or gels formulated in a conventional manner.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compound of (IXa) or (X) is prepared as a transdermal dosage form. In one embodiment, the transdermal formulations described herein comprise at least the following three components: (1) Formula (I), (Ia), (II), (III), (IV) Formulations of compounds of (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X); (2) penetration enhancers; and (3) aqueous Adjuvant. In some embodiments, transdermal formulations include additional components such as, but not limited to, gelling agents, creams, and ointment bases. In some embodiments, transdermal formulations include a fibrous backing, or a non-woven backing, to promote absorption and prevent removal from the skin. In other embodiments, the transdermal formulations described herein are capable of maintaining saturation or supersaturation to promote diffusion to the skin.

  In one embodiment, a formulation suitable for transdermal administration of a compound described herein utilizes a transdermal delivery device and a transdermal delivery patch, and is lipid soluble, dissolved and / or dispersed in a polymer or adhesive. Or an aqueous buffer solution of In one embodiment, such patches are constructed for continuous, pulsatile, or on demand delivery of therapeutic agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like. In one embodiment, the transdermal patch is of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa) Provided a controlled delivery of a compound of (IX), (IXa) or (X). In one embodiment, the transdermal device comprises a bandage comprising a backing member, a reservoir optionally comprising a compound with a carrier, optionally a compound at a rate previously controlled and measured over time. It is in the form of a rate-limiting barrier for delivery to the skin and means for securing the device to the skin.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compounds of (IXa) or (X) are formulated into pharmaceutical compositions suitable for intramuscular, subcutaneous or intravenous injection. In one embodiment, formulations suitable for muscle, subcutaneous or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile injectables. Sterile powder to be reconstituted into a solution or dispersion. Examples of suitable water-soluble and non-water-soluble carriers, diluents, solvents or vehicles are water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor etc.), suitable mixtures thereof, vegetable oils (olive oil) And the like, and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In some embodiments, formulations suitable for subcutaneous injection also include additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid. In some cases, it may also be desirable to include isotonic agents, such as sugar, sodium chloride and the like. Sustained absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

  For intravenous infusion, the compounds described herein are formulated in an aqueous solution, preferably a physiologically compatible buffer such as Hanks's solution, Ringer's solution, or physiological saline buffer. It can be done. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are known.

  Parenteral injection relates to bolus injection or continuous administration. Formulations for injection may be provided in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical compositions described herein may be in a form suitable for injection as a sterile suspension, an aqueous solution or an emulsion in an oily or water-soluble vehicle, suspensions, stabilizers, and It may contain formulator agents such as dispersants. In one embodiment, the active ingredient is in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

  In certain embodiments, delivery systems for pharmaceutical compounds, such as, for example, liposomes or emulsions, may be utilized. In certain embodiments, the compositions provided herein are, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer Also included may be mucoadhesive polymers selected among sodium alginate and dextran.

  In some embodiments, the compounds described herein can be administered topically and include solutions, suspensions, lotions, gels, pastes, medicinal sticks, analgesics, creams, cartilage agents, etc. Can be formulated into various topically administrable compositions. Such pharmaceutical compounds can include solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

<Method of administration and treatment regimen>
In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) and (X) are used for the preparation of a medicament for the treatment of a disease or disorder in a mammal, which benefits from a reduction in androgen receptor activity. A method of treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises, in a therapeutically effective amount to the subject, at least one of the formula (I) Compounds of Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X), or The present invention relates to the administration of pharmaceutical compositions comprising their pharmaceutically acceptable salts, active metabolites, prodrugs, or pharmaceutically acceptable solvates.

  In certain embodiments, compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest the disease or at least one symptom of the disease. Amounts effective for this use will depend on the severity and course of the disease or disorder, prior treatment, the patient's health, weight and drug response, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation clinical trials and the like.

  In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Be done. Such amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, etc. When used in a patient, an amount effective for such use may include the severity and course of the disease, disorder, or disease, prior treatment, the patient's health status and response to drugs, and the judgment of the treating physician. Depends on In one aspect, the prophylactic treatment is of the formulas (I), (Ia), (II), (III), (III), (IV), (V), (VI), to prevent the recurrence of symptoms of the disease or condition. ), (VII), (VIII), (VIIIa), (IX), (IXa), or a pharmaceutical composition comprising a compound of (X) in the past having experienced at least one symptom of the disease being treated Administration to mammals currently in remission.

  In certain embodiments in which the patient's disease is not ameliorated, at the discretion of the physician, administration of the compound may be chronic, ie, to ameliorate or otherwise control or limit the patient's disease or disorder symptoms. It is administered for a long period of time, such as throughout the patient's lifetime.

  In certain embodiments in which the patient's condition is improved, the dose of the drug to be administered may be temporarily reduced or may be temporarily stopped for a period of time (ie, a drug holiday). In certain embodiments, the length of the washout period is, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days Or between 2 days and 1 year, including 28 days or more. The dose reduction during the washout period is, by way of example only, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% , Between 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%, between 10% and 100%.

  Once the patient's symptoms improve, maintenance doses are given as needed. Subsequently, in a specific embodiment, the dosage or frequency of administration, or both, is reduced to a sustained level of the ameliorated disease, disorder or condition, depending on the condition. However, in certain embodiments, the patient needs intermittent treatment over time, due to the recurrence of any symptoms.

  The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host in need of treatment (eg, weight, gender), etc. However, it may be determined, for example, depending on the particular agent being administered, the route of administration, the disease to be treated, and the particular environment surrounding the case, including the subject or host to be treated.

  However, in general, the doses used for adult treatment are typically in the range of 0.01 mg to 5000 mg per day. In one embodiment, the dosage used for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is administered in a single dose, or simultaneously (or in a short time), or at appropriate intervals, such as two, three, four times a day, or It is conveniently provided in divided doses administered as a lower dose.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (V), (VI), (VII), (VIII) as described herein. Suitable daily doses for the compounds of (VIIIa), (IX), (IXa) or (X) are up to about 0.01 to about 10 mg / kg of body weight. In a specific embodiment, the indicated daily doses for large mammals, including but not limited to humans, range from about 0.5 mg to 1000 mg, including but not limited to up to 4 times a day It is conveniently administered in divided doses. In one embodiment, the daily dose is administered in sustained release form. In certain embodiments, unit dosage forms suitable for oral administration contain about 1-500 mg of the active ingredient. In other embodiments, the daily dosage or amount of activity of the dosage form is lower or higher than the ranges set forth herein, based on a number of variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage are varied depending on a number of variables, which are the activity of the compound used, the disease or disorder being treated, the form of administration, the individual Subject requirements include, but are not limited to, the severity of the disease or disorder being treated, and the judgment of the practitioner.

The toxicity and therapeutic effects of such therapeutic regimens are measured by standard pharmaceutical procedures in cell culture or in experimental animals, and such procedures include, but are not limited to, measurement of LD ₅₀ and ED _50. . The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD ₅₀ and ED _50. In certain embodiments, the data obtained from cell culture assays and animal studies are formulated in a therapeutically effective daily dosage range and / or a therapeutically effective single dose for use in mammals, including humans. Used in In some embodiments, the daily dosages of the compounds described herein are within a range of circulating concentrations that include ED50 with minimal toxicity. In certain embodiments, the daily dose and / or single dose will vary within this range, depending on the dosage form employed and the route of administration utilized.

<Combination treatment>
In particular examples, Formulas (I) (Ia) (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), ( It is appropriate to administer at least one compound of IXa) or (X) in combination with another therapeutic agent.

  In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administration of an adjuvant (ie, by itself, the adjuvant comprises a minimal therapeutic effect, but with another therapeutic agent) Together they enhance the overall therapeutic effect for the patient). Alternatively, in some embodiments, the effect experienced by the patient is also by administering one of the compounds described herein, together with another therapeutic agent that also includes a therapeutic effect (including a treatment regimen). Increase.

  In one specific embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), The compounds of (IX), (IXa), or (X) are co-administered with a second therapeutic agent, wherein V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or the compound of (X) and the second therapeutic agent can be a disease, disorder, or Modifies different aspects of the disease, thereby providing greater overall benefits than the administration of either therapeutic agent.

  In all cases, regardless of the disease, disorder or disease being treated, the overall benefit the patient receives may simply be the addition of two therapeutic agents, otherwise the patient may You may receive a synergistic utility.

  In certain embodiments, various therapeutically effective dosages of the compounds disclosed herein may be one or more additional agents, such as an adjuvant, etc., which are therapeutically effective for the compounds disclosed herein. When administered in combination with additional agents, they are used to formulate pharmaceutical compositions and / or used in treatment regimens. The therapeutically effective dosages of drugs and other agents used in combination treatment regimens may be determined by means similar to those described above for the activity itself. Furthermore, the methods of prevention / treatment described herein include the use of metronomic administration, ie, providing low doses more frequently to minimize toxic side effects. In some embodiments, the combination therapy regimen is represented by formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), ( Administration of a compound of VIIIa), (IX), (IXa), or (X) is initiated before, during, or after treatment with a second agent described herein, and treatment with a second agent Or a treatment regimen lasting until any time after completion of treatment with a second agent. Combination therapy regimens may be of the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compound of (IXa) or (X) and the second agent used in combination may be administered simultaneously or at different times, and / or at short or long intervals during the treatment period. Treatment is also included. Combination treatments also include periodic treatments that are started and stopped at various times to assist with the clinical management of the patient.

  It is to be understood that the dosing regimen to treat, prevent or ameliorate the disease for which relief is sought is to be modified according to various factors. Such factors include the disease, disorder or condition in which the subject is afflicted, as well as the subject's age, weight, sex, diet, and health condition. Thus, in some instances, the dosing regimen actually employed differs from the dosing regimen described herein, and in some embodiments deviates from the dosing regimen described herein.

  For the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of concomitant drug used, the particular drug used, the disease or illness being treated, and the like. In further embodiments, when co-administered with one or more therapeutic agents, the compounds provided herein are administered either simultaneously with, or sequentially with, one or more therapeutic agents.

  In combination therapy, the many therapeutic agents (one of which is one of the compounds described herein) are administered in any order or simultaneously. When administration is simultaneous, many therapeutic agents are provided in a single unitary form or in many forms (for example, as a single pill or as two separate pills), to name but one example. Be done. In one embodiment, one of the therapeutic agents is given in multiple doses, and in another embodiment two (or more, if present) are given in multiple doses. In some embodiments of non-co-administration, the timing between multiple administrations varies from 0 weeks or more to less than 4 weeks. Furthermore, the methods, compositions and formulations of the combination are not limited to the use of only two agents. The use of multiple therapeutic combinations is also envisioned.

  Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or And (X) are compounds of formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (VIIIa), (VIII). As with both combinations comprising the compounds IX), (IXa), and (X), the timing of administering the composition comprising the compound is varied before, during, or after the onset of the disease or disorder. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered sequentially to a subject prone to develop a disease or disorder to prevent the onset of the disease or disorder. Be done. In another embodiment, the compounds and compositions are administered to a subject during, or as soon as possible after onset of symptoms. In a specific embodiment, the compounds described herein are as soon as practicable as soon as practicable after the onset of the disease or disorder has been detected or suspected. It is administered for the time that treatment of the disease is required. In some embodiments, the length of time required for treatment is different, and the length of treatment is adjusted to meet the specific needs of each subject. For example, in specific embodiments, a compound or formulation comprising a compound described herein is administered for at least 2 weeks, about 1 to about 5 years.

<Typical drugs for use in combination therapy>
In some embodiments, a method for the treatment of an androgen receptor dependent or androgen receptor mediated disease or disorder, such as a proliferative disease comprising cancer, is a compound of formula (I), (Ia), (II) (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or a compound of (X) selected from The step of administering to a mammal in combination with one additional agent, the additional agent being, by way of example only, alemtuzumab, arsenite, asparaginase (pegylated or not pegylated) , Bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicin / idalubicin, irinotecan, fludarabine, 5- Classification of drugs including luolouracil, gemtuzumab, methotrexate, taxol, temozolomide, thioguanine, or hormones (antiestrogens, antiandrogens, or gonadotropin releasing hormone analogs), interferons such as alpha interferon, busulfan or melphalan or Containing nitrogen mustard such as mechlorethamine, retinoid such as tretinoin, topoisomerase inhibitor such as irinotecan or topotecan, tyrosine kinase inhibitor such as gefitinib or imatinib, or allopurinol, filgrastim, granisetron / ondansetron / palonosetron, dronabinol , Selected from agents that treat signs or symptoms induced by such treatment It is.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compound of (IXa) or (X) is administered or formulated in combination with one or more anticancer agents. In some embodiments, one or more anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossypol, genasense, polyphenol E, chlorofucin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor related apoptosis inducing ligand (TRAIL), 5-aza -2'-deoxycytidine all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, geldanamycin, 17-N-allylamino-17- demethokigeldanamycin (17-AAG), flavopyridol, LY 294002, Bortezomib, trastuzumab, BAY 11-7082, PKC412 or PD184352, paclitaxel, and an analogue of paclitaxel. Compounds with a basic taxane backbone as a common structural feature have been shown to have the ability to arrest cells at the G2M stage by means of stable microtubules, and in combination with the compounds described herein cancer. It can also help to treat.

  Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), and Further examples of anti-cancer agents for use in combination with the compounds of (X) are inhibitors of mitogen-activated protein kinase signaling such as, for example, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43 -9006, wortmannin or LY 294002; Syk inhibitor; mTOR inhibitor; and antibodies (e.g. Rituxan).

  Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or Other anticancer agents for use in combination with the compound (X) include one or more of abiraterone, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; Aldesleukin; altretamine; ambomycin; amethantrone acetate (amethantrone acetate); aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperrin; azacytidine; azetata; azotomycin (azotomycin) Batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; biselecin; bleomycin sulfate; bleomycin sodium; bropirimine; busulfan; Calvisin; cedefingol (cedefingol); chlorambucil; cilolemycin (clisnatol mesylate); cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin (dexormaplatin); Guanine (dezaguanine); desaguanine mesylate (dezaguanine mesylate); diazisorbone; doxorubicin; doxorubicin hydrochloride; droloxifene hydrochloride; droloxifene citrate; ; Enloplatin (enloplatin); enpromate (enpromate); epipropidine; epirubicin hydrochloride; elbrosol; esorubicin hydrochloride (esorubicin hydrochloride); estramustine sodium; estramustine phosphate sodium; etanidazole; etoposide; phosphate etoposide; Fluzaurin phosphate; fluorouracil phosphate; fluroiocitabine; fosquidone; fostriceone sodium; gemcitabine hydrochloride; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; imimofosine (iimofosin); Interferon α-2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-la; Interferon γ-lb; Iproplatin; Irinotecan Hydrochloride; Letrozole; Leuprolide Acetate (leupro) ide acetate); liarozole hydrochloride; lometelexole sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogalil; Methotrexate sodium; methoprine; metredepa; mitindomid; mitocalcin; mitocromine; mitogyrin; mitomycin; mitosper; mitotane; mitotane hydrochloride; Pegaspalgase; periomycin; pentamustine (pentamustine); pepromycin sulfate; perfosfamide (perfosfamide); pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; promestane; porfimer sodium; porphyromycin Prodhammycin hydrochloride; puromycin; puromycin; pyrazofurin; ribopurine; logretimido; safingol; safingol hydrochloride; semustine; simmusten; simtrazene; sparphosate sodium; sparsomycin; spirogermanium hydrochloride; Platin; Streptonigrin; Strepto Slofenur (sulfurenur); talisomican sodium: tecogaran sodium; tegafur; teloxotrope hydrochloride; temoporphin; teniposide; tricitrixine phosphate; trimetrexate trimetrexate glucuronate (trimetrexate glucuronate); triptorelin, tubrosol hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin sulfate; vincristine sulfate; vindesine sulfate; vindesine sulfate; vinepidine sulfate Vinleurosine sulfate Vinorelbine tartrate; sulfate Binroshijin; sulfate vinzolidine (vinzolidine sulfate); vorozole; Zenipurachin; zinostatin; zorubicin.

  Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or , Yet another anticancer agent for use in combination with the compound of (X), an alkylating agent, an antimetabolite, a natural product or a hormone, for example, nitrogen mustard (eg, mechloroethamine, cyclophosphamide, Chlorambucil etc.), alkyl sulfonates (eg busulfan), nitrosoureas (eg carmustine, lomustine etc.), or triazenes (dacarbazine etc.). Examples of metabolic antagonists include, but are not limited to, folate analogs (eg, methotrexate) or pyrimidine analogs (eg, cytarabine), purine analogs (eg, mercaptopurine, thioguanine, pentostatin).

  Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), and Examples of natural products for use in combination with the compounds of (X) include, but are not limited to, vinca alkaloids (eg, vinblastine, vincristine), epipodophyllotoxins (eg, etoposide), antibiotics (eg, daunorubicin) , Doxorubicin, bleomycin), enzymes (eg, L-asparaginase), or biological response modifiers (eg, interferon alpha).

  Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa), or Examples of alkylating agents for use in combination with the compounds of (X) include, but are not limited to, nitrogen mustards (eg, mechlorethamine, cyclophosphamide, chlorambucil, etc.), ethyleneimines and methylmelamines (eg, For example, hexamethylmelamine, thiotepa), alkyl sulfonates (eg, busulfan), nitrosoureas (eg, carmustine, lomustine, semustine, streptozocin, etc.), or triazene (eg, decarbazine).

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), and (X) compounds in combination with anti-estrogen agents (eg, tamoxifen), anti-androgen agents (eg, bicalutamide, flutamide), gonadotropin-releasing hormone analogs (eg, leuprolide) Used to treat

  Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (eg, cisplatin, carboplatin), anthracenediones (eg, mitoxantrone), Substituted ureas (eg, hydroxyurea), methylhydrazine derivatives (eg, procarbazine), inhibitors of the adrenal cortex (eg, mitotane, aminoglutethimide).

  Examples of anti-cancer agents that act thereby by arresting cells in the G2M phase by stabilized microtubules include, without limitation, the following marketed drugs and drugs under development: Elbrosol, Dolastatin 10, Mibobulin isethionate (Mivobulin isethionate ), Vincristine, NSC-639829, discodermolide, ABT-751, altorhyrtins (Altorhyrtins (such as altriltin A and altrillin C)), spongystatin (spongistatin 1, spongystatin 2, spongystatin 3) Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, Spongistatin 9, etc., semadotin hydrochloride (Cemadotin hydrochlo) epothilone (epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-amino epothilone B, 21- Hydroxyepothilone D, 26-fluoroepothilone), auristatin (Auristatin) PE, soburidotin, vincristine sulfate, cryptophysin 52, vitilebamide (Vitilevuamide), tubulysin A, canadensol (Canadensol), centaureidin (Centaureidin) ), Oncocidin A1 Fisianolide B, Laurimalide (Laulimalid) e) Narcosine, Nascapine (Nascapine), hemiasterine, vanadocene acetylacetonate, Indanocine Eleutherobins (Indanocine Eleutherobins) (Desmethyleleutherobin), Desacetyl Eloitherobin (Desaetyleleutherobin), Isoeroitherobins (Lsoeleutherobin) A, and Z-eleoterobin etc., caribeoside (Caribaeoside), caribeoolin (Caribaeolin), halichondrin B, diazonamide A, tacachanolide A, diozostatin (Diozostatin), (-)-phenylahistin (Phenylah) STIN), Mioseberin (Myoseverin) B, resveratrol statins (Resverastatin sodium phosphate.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), The compound of (IXa) or (X) is a thrombolytic agent (eg, alteplase anistreplase, streptokinase, urokinase or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (eg, dabigatran) Etexilate), factor Xa inhibitors (eg fondaparinux, draparinx, rivaroxaban, DX-1065a, otamixaban, LY517717 or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel) LY640315), ximelagatran, or be co-administered with BIBR 1048.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of formulas (I), (Ia), ((IXa)) (II) (III) (IV), (V) (VI) (VII) (VIII) ) (VIIIa) (IX) or a compound of (X), an anticancer agent and / or used in combination with an antiemetic to treat nausea or vomiting resulting from the use of radiation therapy.

  Antiemetics include, but are not limited to, neurokinin-1 receptor antagonists, 5HT3 receptor antagonists (such as ondansetron, granisetron, tropisetron, palonosetron, and zatisetron), GABA B receptor agonists (such as baclofen), Corticosteroids (such as dexamethasone, prednisone, prednisolone or others), dopamine antagonists (including, but not limited to, domperidone, droperidol, haloperidol, chlorpromazine, promethazine, prochlorperazine, metoclopramide), antihistamines (limited H1 histami such as cyclidine, diphenhydramine, dimenhydrinate, meclidine, promethazine, hydroxyzine etc. Receptor antagonists), but cannabinoids (not limited to, Cannabis, Marinol, etc. dronabinol), and, although other ones (but are not limited to, trimethoprim-benzamide; including ginger, Emetrol, propofol, etc.).

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa) or (X) are used in combination with agents useful for the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoietin receptor activator (such as epoetin-α).

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa) or (X) are used in combination with agents useful for the treatment of neutropenia. Examples of agents useful for the treatment of neutropenia include, but are not limited to, hematopoietic growth factors that regulate neutrophil formation and function, such as human granulocyte colony stimulating factor (G-CSF). Examples of G-CSF include filgrastim.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) compounds are administered with corticosteroids. Corticosteroids include, but are not limited to: betamethasone, prednisone, alclomethasone, aldosterone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortron, clopredol, cortisone, cortibazole, deflazacolto Deoxycorticosterone, Desonide, Desoxymethasone, Desoxycortone, Dexamethasone, Diflorazone, Diflucortorone, Diflupredrone, Fluorchlorone, Fludrocortisone, Fludroxicortide, Flumethasone, Flunisolone, Fluocinolone Acetonide, Fluocinonide, fluocortin, fluocortorone, fluorometholone, fluperolone, fluprednisden, fluti Zon, formocotal, halcinonide, halometasone, hydrocortisone / cortisol, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butepolate, hydrocortisone butyrate, loteprednol, medrizone, meprednisone, methylprednisolone, methylprednisolone aceponate, folate ester, parazone Bates, prednisone / prednisolone, rimexolone, thixocortol, triamcinolone and urobetasol.

  In one embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) , (IXa), or (X) is administered to a mammal in combination with a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, Fenoprofen calcium, flurbiprofen (flurobiprofen), ibuprofen, ketoprofen, nabutone (nabutone), ketorolac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamic acid, meclofenamate sodium Mefenamic acid, piroxicam, meloxicam, COX-2 specific in Bitter (celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337, and, including NS398, but not limited to) a.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) The compounds of (IXa) and (X) are co-administered with an analgesic.

  In some embodiments, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa), or (X) are used in combination with radiation therapy (or radiation therapy). Radiation therapy is the treatment of cancer and other diseases by ionizing radiation. Radiation therapy can be used to treat localized solid tumors such as cancers of the skin, tongue, larynx, brain, chest, prostate, colon, uterus and / or cervix. Radiation therapy can be used to treat leukemia and lymphoma (hematopoietic cells and cancers of the lymphatic system, respectively).

  A technique for irradiating cancer cells is to place radioactive implants directly in the tumor or body cavity. This is called internal radiation therapy (narrow radiation therapy, interstitial radiation, and intracavitary radiation are types of internal radiation therapy). Because internal radiation therapy is used, radiation doses are concentrated in small areas and patients are hospitalized for several days. Internal radiation therapy is frequently used for cancers of the tongue, uterus, prostate, colon and neck.

  The terms "radiotherapy" or "ionizing radiation" include all forms of radiation including, but not limited to, alpha, beta, and gamma radiation and ultraviolet radiation.

<Kit / Product>
Kits and products are also described herein for use in the therapeutic applications described herein. Such kits can include a carrier, a package, or a container partitioned to contain one or more containers, such as vials and tubes, each of which is described herein. Includes one of the individual elements used in the method. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container is formed, for example, of any acceptable material such as glass or plastic.

  For example, the container can include one or more compounds described herein, optionally in a composition or in combination with another agent as described herein. The container optionally has a sterile access port (for example the container may be a solution bag for intravenous injection or a vial provided with a stopper pierceable by a hypodermic injection needle). Such kits comprise the compound with identification instructions, labels, or instructions for use in the methods described herein.

The kit typically comprises one or more additional containers, each container being one or more of a variety of materials desired from a commercial and user perspective for use of the compounds described herein. (Eg, with reagents, optionally in concentrated form and / or in devices). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, fillers, injection needles, syringes; delivery devices, packages, containers, vials with contents and / or instructions for use And / or a label on the tube, and a package insert including instructions for use.
A series of instructions are also typically included.

  The label may be on or attached to the container. The label is on the container if the letters, numbers or other characters forming the label are attached, molded or etched into the container body. The label may be affixed to the container if the label is present inside the container or carrier holding the container, for example, as a package insert. A label may be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for using the contents, such as in the methods described herein.

  These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein.

(Synthesis of compounds)
(Intermediate 1)
5-amino-3- (trifluoromethyl) picolinonitrile step 1: 5-iodo-3- (trifluoromethyl) pyridin-2-ol

  A mixture of 5-iodo-3- (trifluoromethyl) pyridin-2-ol (21.4 g, 0.13 mmol) and NIS (29.5 g, 0.13 mmol) in acetonitrile (300 mL) is heated to 80 ° C. 6 Heated for time. The reaction mixture was cooled to room temperature and a saturated solution of sodium bicarbonate was added. The precipitated solid was filtered off and the acetonitrile was removed in vacuo. The aqueous layer is extracted with EtOAc (4x), the organics are combined, washed with a saturated aqueous solution of sodium thiosulfate, dried over sodium sulfate and concentrated to dryness, as a yellow solid, 24 g of 5- Iodo-3- (trifluoromethyl) pyridin-2-ol was obtained.

Step 2: 2-Chloro-5-iodo-3- (trifluoromethyl) pyridine

A mixture of 5-iodo-3- (trifluoromethyl) pyridin-2-ol (53 g, 0.18 mmol) and POCl ₃ (67 mL, 0.73 mmol) in DMF (50 mL) was heated to 110 ° C. for 4 hours . The reaction mixture was cooled to room temperature and then poured slowly into an ice / water bath. The brown solid was filtered and washed with water. Then it is dissolved in DCM, washed with a saturated aqueous solution of sodium thiosulphate (2x), dried over sodium sulphate and concentrated to dryness, as a pale yellow solid, 47 g of 2-chloro -5-iodo-3- (trifluoromethyl) pyridine was obtained.

Step 3: 6-Chloro-N- (4-methoxybenzyl) -5- (trifluoromethyl) pyridin-3-amine

The oil bath was preheated to 130 ° C. 2-Chloro-5-iodo-3- (trifluoromethyl) pyridine (47 g, 152.8 mmol) in toluene (500 mL), (4-methoxyphenyl) methanamine (23.8 mL, 183.4 mmol), xanthophos (2 A mixture of .6 g, 4.58 mmol) and NaOtBu (22 g, 229.2 mmol) was stirred at room temperature with nitrogen bubbling for 5 minutes. Then Pd ₂ (dba) ₃ (2.8 g, 3.05 mmol) was added and the reaction mixture was refluxed for 2 hours. The mixture was cooled to room temperature and filtered through a pad of celite. The pad of celite was washed with toluene and the filtrate was concentrated. The residue obtained was dissolved in EtOAc and the organic layer was washed with water (4 ×) then evaporated to dryness. The resulting dark oil was dissolved in DCM and hexanes was added with rotation until a brown solid precipitated. The brown solid is filtered, washed with hexane, dried and 38.8 g (80%) of 6-chloro-N- (4-methoxybenzyl) -5- (trifluoromethyl) pyridine as a brown solid -3- amine was obtained.

  The filtrate is purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give an additional 4 g of 6-chloro-N- (4 as an orange solid (total yield: 42.8 g) -Methoxybenzyl) -5- (trifluoromethyl) pyridin-3-amine was obtained.

Step 4: 5-((4-methoxybenzyl) amino) -3- (trifluoromethyl) picolinonitrile

The oil bath was preheated to 180 ° C. 6-Chloro-N- (4-methoxybenzyl) -5- (trifluoromethyl) pyridin-3-amine (19.45 g, 61.55 mmol) in DMF (250 mL), Zn (CN) ₂ (8.7 g , 73.86 mmol), and dppf (6.8 g, 12.31 mmol) were stirred at room temperature with nitrogen bubbling for 5 minutes. Then Pd ₂ (dba) ₃ (2.8 g, 3.07 mmol, 0.05 eq) was added and the reaction mixture was placed in a preheated bath. The bath temperature dropped to 160 ° C. When the bath temperature reached 170 ° C. (takes 20 minutes), the mixture began to reflux. Reflux for 10 minutes. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The pad of celite was washed with EtOAc. The solvent was removed using a rotovap connected to a high vacuum pump. The black residue was partitioned between EtOAc and water. An orange solid (some dppf byproducts) precipitated which was filtered and washed with EtOAc. The organic layer was washed with brine (2 ×), dried over sodium sulfate and concentrated to dryness. The black residue was dissolved in DCM and loaded onto a silica gel plug. The plug was washed with DCM (to remove some of the fast eluting impurities), followed by 1: 1 EtOAc / hexane (to move the desired one). The fractions containing the desired ones are combined and evaporated to dryness and the residue obtained is purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give a reddish thick oily residue 15 g of 5-((4-methoxybenzyl) amino) -3- (trifluoromethyl) picolinonitrile were obtained.

Step 5: 5-Amino-3- (trifluoromethyl) picolinonitrile

5-((4-Methoxybenzyl) amino) -3- (trifluoromethyl) picolinonitrile (15 g, 49.02 mmol) was taken up in DCM (30 mL) and TFA (50 mL) was added. The resulting reaction mixture was stirred at room temperature for 3 hours (until done by LC-MS). The solvent and TFA were removed in vacuo and MeOH was added to the residue.
The beige solid not soluble in MeOH was filtered and washed with MeOH. The filtrate was evaporated to dryness and the residue was partitioned between EtOAc and a saturated solution of sodium hydrogen carbonate. The organic layer was washed twice more with saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to dryness. The residue was dissolved in DCM and hexane was rotated until a yellow solid precipitated. The solid was filtered and washed with hexane to give 7.2 g of 5-amino-3- (trifluoromethyl) picolinonitrile as a pale yellow solid.

(Intermediate 2)
5-Amino-3-methylpicolinonitrile Step 1: 3-Methyl-5-nitropicolinonitrile

  A mixture of tetrabutylammonium nitrate (17 g, 55.1 mmol) and trifluoroacetic anhydride (7.6 mL, 55.1 mmol) in DCM (50 mL) was added to 3-methylpicolinonitrile (5 g) in DCM (100 mL) , 42.4 mmol) was slowly added to the cooled (0 ° C.) solution, and the resulting mixture was stirred for 3 days (a temperature that allowed to warm to room temperature). A saturated solution of sodium hydrogen carbonate (80 mL) was added and the mixture was stirred at room temperature for 1 hour. The two layers were separated and the aqueous layer was extracted with DCM (2x). The organics were combined, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give 2.9 g of 3-methyl-5-nitropicolinonitrile as a pale yellow solid.

Step 2: 5-amino-3-methylpicolinonitrile

  A mixture of 3-methyl-5-nitropicolinonitrile (2.9 g, 17.8 mmol) and pd / C (cat.) In MeOH (60 mL) was hydrogenated with a balloon of hydrogen overnight. The pd / C was removed through a pad of celite and the filtrate was evaporated to dryness to give 2.2 g of 5-amino-3-methylpicolinonitrile as a greenish solid.

(Intermediate 3)
3- (Trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-amine Step 1: 6-Chloro-3- (trifluoromethyl)-[1,2,4] Triazolo [4,3-b] pyridazine

  A mixture of 3-chloro-6-hydrazinylpyridazine (3.3 g, 22.8 mmol) in TFA (60 mL) was heated to 85 ° C. for 18 hours. The reaction mixture was cooled to room temperature and the TFA was removed in vacuo. The residue is partitioned between DCM and saturated aqueous sodium hydrogen carbonate, the organic phase is washed with a saturated solution of sodium hydrogen carbonate (3 ×), dried over sodium sulphate and evaporated to dryness, beige 2.8 g of 6-chloro-3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazine were obtained as a solid.

Step 2: 3- (Trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-amine

  6-Chloro-3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazine (1.14 g, 5.1 mmol) and ammonium hydroxide (10 mL) in THF (10 mL) The mixture was heated to 60.degree. C. for 18 hours. The reaction mixture was cooled to room temperature and water and ETOac were added. The aqueous layer is extracted with EtOAc (4x), the organics are combined, dried over sodium sulfate, evaporated to dryness and 1 g of 3- (trifluoromethyl)-[1,2,4] as a beige solid. The triazolo [4,3-b] pyridazin-6-amine was obtained.

(Intermediate 4)
6-Amino-2- (trifluoromethyl) picolinonitrile

DMA (12 mL) of 5-bromo-6- (trifluoromethyl) pyridin-2-amine _{(3.0g, 12.3mmol), Zn (} CN) 2 (0.81g, 6.9mmol), Pd 2 ( dba) ₃ (0.57 g, 0.6 mmol) and xanthophos (0.72 g, 1.2 mmol) were placed in a shielded tube. The mixture was degassed with argon and stirred at 160 ° C. for 20 hours. The mixture was poured into water and extracted with EtOAc (2x). The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel eluting with 3: 1 EtOAc / hexane to give 1.9 g of 6-amino-2- (trifluoromethyl) nicotinonitrile as a solid .

(Intermediate 5)
3- (Trifluoromethyl)-[2,3'-bipyridine] -5-amine Step 1: N- (4-methoxybenzyl) -3- (trifluoromethyl)-[2,3'-bipyridine] -5 -Amines

6-Chloro-N- (4-methoxybenzyl) -5- (trifluoromethyl) pyridin-3-amine (Intermediate 1, step 3, 1.2 g, 3.8 mmol) in 1,4-dioxane (100 mL) ) and 3- (Jiechiruboriru) pyridine (0.613 g, to a solution of 4.17 _mmol), was added _{K 3 PO 4 (2.52g, 9.48mmol} ). The mixture was degassed and then flushed with nitrogen before adding Pd ₂ (dba) ₃ (173 mg, 0.02 mmol) and xanthophos (0.218 mg, 0.04 mmol). The mixture was heated to 105 ° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate is concentrated in vacuo and the residue is purified by column chromatography over silica gel using EtOAc / PE = 1, 1 g of N- (4-methoxybenzyl) -3- (trifluoromethyl)- [2,3'-bipyridine] -5-amine was obtained.

Step 2: 3- (Trifluoromethyl)-[2,3'-bipyridine] -5-amine

  The title compound is described for intermediate 1, step 5, using N- (4-methoxybenzyl) -3- (trifluoromethyl)-[2,3'-bipyridine] -5-amine as the starting material Was synthesized to

(Intermediate 6 (Isothiocyanate Method A))
5-isothiocyanato (Isothiocyanato) -3-methylpicolinonitrile

Thiophosgene (0.24 mL, 3.1 mmol), stirred biphasic of 5-amino-3-methylpicolinonitrile (Intermediate 2, 275 mg, 2.07 mmol) in CHCl ₃ (6 mL) / water (10 mL) The resulting orange mixture was stirred at room temperature overnight. The two layers were separated and the aqueous layer was extracted with DCM (3x).
Combine the organics, wash with a saturated solution of sodium bicarbonate (2x), dry over sodium sulfate and evaporate to dryness to give 300 mg of 5-isothiocyanato-3-methylpicolinonitrile as an orange solid The

(Intermediate 7)
6-Isothiocyanato-2- (trifluoromethyl) nicotinonitrile

  A mixture of 6-amino-2- (trifluoromethyl) nicotinonitrile (648 mg, 3.5 mmol) and thiophosgene (0.4 mL, 5.2 mmol) in DCE (8 mL) was heated to 80 ° C. overnight. The mixture was cooled to room temperature and diluted with DCM / water. The two layers were separated and the aqueous layer was extracted with DCM (3x). The organics are combined, washed with a saturated solution of sodium bicarbonate (2x), dried over sodium sulfate, evaporated to dryness and 521 mg of 6-isothiocyanato-2- (trifluoromethyl) nicotinonitrile as a red oil (Purity 70%) was obtained.

(Intermediate 8)
6-isothiocyanato-3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazine

Thiophosgene (1 mL, 12.7 mmol), 3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-amine in pyridine (10 mL) and THF (15 mL) 860 mg (4.23 mmol) was added to the solution and the resulting dark mixture was stirred at room temperature for 2 hours. The dark mixture was partitioned between EtOAc and 1 M HCl. The organic layer is washed with 1 M HCl (2 ×), dried over sodium sulfate, evaporated to dryness, 545 mg of 6-isothiocyanato-3- (trifluoromethyl)-[1,2,4 as a dark purple solid. ] Triazolo [4,3-b] pyridazine (purity 60%) was obtained. LCMS [M + 1] ⁺ 278.5 (adduct of OMe).

(Intermediate 9 (isothiocyanate method B))
4-isothiocyanatoisoquinoline-1-carbonitrile

  A mixture of 4-aminoisoquinoline-1-carbonitrile (500 mg, 2.95 mmol) and thiophosgene (0.34 mL, 4.44 mmol) in DMA (5 mL) was stirred at room temperature overnight. The mixture was diluted with EtOAc / water. The two layers were separated and the aqueous layer was extracted with EtOAc (3x). The organics were combined, washed with a saturated solution of sodium bicarbonate (2x), dried over sodium sulfate and evaporated to dryness to give 553 mg of 4-isothiocyanatoisoquinoline-1-carbonitrile as an orange oil .

  Isothiocyanate intermediates 10-16, according to the conditions indicated, suitable amines (amines were either commercially available, either synthesized in the section of the intermediates or synthesized from published procedures) Synthesized from (see footnote).

(Intermediate 17)
4-((2- (Pyridin-4-yl) ethyl) sulfonyl) aniline Step 1: 4- (2-((4-nitrophenyl) thio) ethyl) pyridine

Acetonitrile (150 mL) solution of 2- (pyridin-4-yl) ethanethiol hydrochloride (3.84 g, 21.8 mmol, 4-fluoro-1-nitrobenzene (6.12 g, 43.3 mmol)), and _K 2 CO A mixture of ₃ (9.0 g, 65.1 mmol) was refluxed overnight. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue is purified by column chromatography on silica gel (EtOAc / PE = 1/1) and 2.0 g of 4- (2-((4-nitrophenyl) thio) ethyl) pyridine as a pale yellow solid I got

Step 2: 4- (2-((4-nitrophenyl) sulfonyl) ethyl) pyridine

H ₂ O ₂ (30%, 5 mL) in a solution of 4- (2-((4-nitrophenyl) thio) ethyl) pyridine (338 mg, 1.30 mmol) in acetic acid (20 mL) heated at 60 ° C. Add dropwise and the resulting mixture was stirred at 60 ° C. for 30 minutes. The mixture was poured into saturated Na ₂ CO ₃ (100 mL) and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica gel (EA / PE = 1/3) to give 270 mg of 4- (2-((4-nitrophenyl) sulfonyl) ethyl) pyridine as a white solid .

Step 3: 4-((2- (Pyridin-4-yl) ethyl) sulfonyl) aniline

A mixture of 4- (2-((4-nitrophenyl) sulfonyl) ethyl) pyridine (210 mg, 0.76 mmol) and 10% pd / C (100 mg) in EtOH (100 mL) under an atmosphere of H ₂ (balloon) The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue is purified by column chromatography on silica gel (MeOH / DCM = 1/50) to give 100 mg of 4-((2- (pyridin-4-yl) ethyl) sulfonyl) aniline as a white solid The

(Intermediate 18)
4-((Methyl (pyridin-4-ylmethyl) amino) methyl) aniline Step 1: N- (4-Nitrobenzyl) -1- (pyridin-4-yl) methanamine

1,2-dichloroethane (40.0 mL) solution of 4-nitrobenzaldehyde (3.0g, 19.8mmol), 4- pyridyl methylamine (2.36g, 21.8mmol), and NaBH ₃ CN (1.75g, The mixture of 27.7 mmol) was stirred at room temperature for 36 hours and then concentrated to dryness. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 ×). The combined organics were washed with brine (2 ×), dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (MeOH / DCM = 1/400) and 1.3 g of N- (4-nitrobenzyl) -1- (pyridin-4-yl) methanamine as red oil I got

Step 2: N-Methyl-N- (4-nitrobenzyl) -1- (pyridin-4-yl) methanamine

  The title compound was synthesized as described in the previous step using N- (4-nitrobenzyl) -1- (pyridin-4-yl) methanamine and (HCHO) n as starting materials.

Step 3: 4-((Methyl (pyridin-4-ylmethyl) amino) methyl) aniline

  The title compound was synthesized as described for Intermediate 17, step 3, using N-methyl-N- (4-nitrobenzyl) -1- (pyridin-4-yl) methanamine as the starting material.

(Intermediate 19 (Aminonitrile Synthesis Method A))
1-((3-Fluoro-4-hydroxyphenyl) amino) cyclobutanecarbonitrile

  Sodium cyanide (2.5 g, 50.8 mmol), 4-amino-2-fluorophenol (4.3 g, 33.9 mmol) and acetic acid (3 3.9 mmol) in acetic acid (99%, 30 mL) tethered to a NaOH scrubber .8 mL, 50.8 mmol) was added to the mixture and the resulting mixture was stirred at room temperature for 6 hours. The mixture was poured into water and the aqueous layer was extracted with EtOAc (3 ×). The organics were combined, washed with a saturated solution of sodium bicarbonate (4x), dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to yield 4.8 g of 1-((3-fluoro-4-hydroxyphenyl) amino) cyclobutane as a beige solid. Obtained carbonitrile.

(Intermediate 20 (Aminonitrile Synthesis Method B))
Ethyl 4-((1-cyanocyclobutyl) amino) -2-fluorobenzoate

  Ethyl 4-amino-2-fluorobenzoate (3.25 g, 17.8 mmol) and cyclobutanone in acetic acid (99%, 40 mL) tethered to a sodium hydroxide (1.3 g, 26.6 mmol) in a scrubber of NaOH To a mixture of (2 mL, 26.6 mmol), the resulting mixture was heated to 80 ° C. overnight. The mixture was cooled to room temperature and poured into water. The pink precipitate was filtered, washed with water and redissolved in DCM (100 mL). The organic layer is washed with a saturated solution of sodium bicarbonate (4x), dried over sodium sulfate, evaporated to dryness, 3.9 g of ethyl 4-((1-cyanocyclobutyl) amino as an orange solid. ) -2-Fluorobenzoate was obtained.

(Intermediate 21 (amino nitrile synthesis method C))
4-((1-Cyanocyclobutyl) amino) -2-fluoro-N-methylbenzamide

  Sodium cyanide (5.8 g, 119 mmol), 4-amino-2-fluoro-N-methylbenzamide (5 g, 29.8 mmol) in AcOH (90%, 25 mL) and EtOH (25 mL) tethered to a NaOH scrubber ) And cyclobutanone (4.4 mL, 59.5 mmol) and the resulting mixture was heated to 80 ° C. overnight. The mixture was cooled to room temperature and poured into water. The yellow precipitate was filtered, washed with water and dried to give 6.5 g of 4-((1-cyanocyclobutyl) amino) -2-fluoro-N-methylbenzamide as a pale yellow solid.

(Intermediate 22 (amino nitrile synthesis method D))
1-((2,6-difluorophenyl) amino) cyclobutanecarbonitrile

  A mixture of 2,6-difluoroaniline (0.5 g, 3.9 mmol), TMSCN (0.72 mL, 5.8 mmol), and cyclobutanone (0.43 mL, 5.8 mmol) was heated to 90 ° C. overnight. The mixture was poured into water and the aqueous layer was extracted with EtOAc (3 ×). The organics were combined, washed with brine (2x), dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-20% EtOAc / hexane to give 0.7 g of 1-((2,6-difluorophenyl) amino) cyclobutanecarbo as a colorless fatty oil Obtained the nitrile.

(Intermediate 23 (amino nitrile synthesis method E))
4-((2-Cyanopropan-2-yl) amino) -2-fluoro-N-methylbenzamide

  4-Amino-2-fluoro-N-methylbenzamide (2 g, 11.9 mmol) in DCM (20 mL), TMSCN (2.2 mL, 17.9 mmol), TMSOTf (0.1 mL, 0.6 mmol), and acetone The mixture of (10 mL, 140 mmol) was stirred at room temperature overnight. The white solid is filtered, washed with a small amount of DCM, dried and 1.12 g of 4-((2-cyanopropan-2-yl) amino) -2-fluoro-N-methylbenzamide as a white solid I got

(Intermediate 24)
1- (4- (Pyridin-4-yloxy) phenylamino) cyclobutanecarbonitrile

Sodium cyanide (395 mg, 8.06 mmol) in a microwave vial, 4- (Pyridin-4-yloxy) aniline (500 mg, 2.69 mmol) in AcOH (99%, 6 mL) and cyclobutanone (376 mg, 5 .37 mmol) was added to the mixture. The reaction mixture was irradiated with microwave (Biotage) at 120 ° C. for 30 minutes. The pale yellowish solution was concentrated to dryness. The residue was diluted with water and extracted with EtOAc (2x). The combined organic layers were dried over MgSO ₄ and concentrated to dryness to give 463 mg (65%) of 1- (4- (pyridin-4-yloxy) phenylamino) -cyclobutanecarbonitrile as a yellow fatty oil .

(Intermediate 25)
2-((4-hydroxyphenyl) amino) -2-methylpropane nitrile

  A mixture of 4-aminophenol (1 g, 9.17 mmol) and magnesium sulfate (4 g) in 2-hydroxy-2-methylpropane nitrile (10 mL) was heated to 80 ° C. for 2 hours. Ice / water was added to the cooling mixture and stirred for 30 minutes. The precipitated white solid was filtered, washed with water and dried to give 1.2 g (74%) of 2-((4-hydroxyphenyl) amino) -2-methylpropane nitrile as a white solid .

  Intermediates 26-107, according to the conditions indicated, from suitable amines (either amines were commercially available, either synthesized in the section of the intermediates or synthesized from published procedures) and ketones Synthesized (see footnote).

(Intermediate 108)
4-((4,4,5,5,5-pentafluoropentyl) thio) butano-1-ol step 1: 4- (benzyloxy) butyl methanesulfonic acid

Methanesulfonyl chloride (1 mL, 13.3 mmol) was cooled to 4- (benzyloxy) butano-1-ol (2 g, 11.1 mmol) and triethylamine (1.9 mL, 13.3 mmol) in DCM (20 mL) Add to the (0 ° C.) solution and stir at 0 ° C. for 1 hour. HCl (1 M) was added to the reaction mixture and the aqueous layer was extracted with DCM (2 ×). The organics were combined, dried over sodium sulfate and evaporated to dryness to give 4- (benzyloxy) butyl methanesulfonic acid as a yellow fatty oil. LCM [M + 1] ⁺ 259.5.

Step 2: 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate

  4,4,5,5,5-Pentafluoropentan-1-ol (1 g, 5.6 mmol) in DCM (20 mL), p-toluenesulfonyl chloride (1.3 g, 6.8 mmol), and triethylamine (1 A mixture of .2 mL, 8.4 mmol) was stirred at room temperature for 18 hours. Water was added to the reaction mixture, the two layers separated and the aqueous layer extracted with DCM (2x). The organics were combined, dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-20% EtOAc / hexane to give 1.7 g of 4,4,5,5,5-pentafluoropentyl 4- as a colorless fatty oil. Methyl benzene sulfonate was obtained.

Step 3: 2- (4,4,5,5,5-pentafluoropentyl) isothiuronium 4-methylbenzenesulfonate

A mixture of 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate (1.7 g, 5.1 mmol) and thiourea (430 mg, 5.6 mmol) in ethanol (20 mL), 18 Refluxed for time. The mixture was cooled to room temperature and most of the ethanol was removed in vacuo. Hexane and Et ₂ O were added until a white precipitate began to form, and the mixture was left at room temperature for 30 minutes. The white solid is filtered, washed with hexane, dried and 1.7 g of 2- (4,4,5,5,5-pentafluoropentyl) isothiuronium 4-methylbenzenesulfonate as a white solid Obtained. LCM [M + 1] ⁺ 237.4.

Step 4: (4- (benzyloxy) butyl) (4,4,5,5,5-pentafluoropentyl) sulfane

4- (benzyloxy) butyl methanesulfonic acid (759 mg, 2.9 mmol) in DMF (20 mL), 2- (4,4,5,5,5-pentafluoropentyl) isothiuronium 4-methylbenzenesulfonate A mixture of (1.2 g, 2.9 mmol), NaOH (5 M, 5 mL) was stirred at room temperature for 4 hours. EtOAc was added to the reaction mixture and the organic layer was washed with brine (2x), dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-20% EtOAc / hexane to give 960 mg of (4- (benzyloxy) butyl) (4,4,5,5, as a yellow fatty oil 5-pentafluoropentyl) sulfane was obtained. LCM [M + 1] ⁺ 357.5.

Step 5: 4-((4,4,5,5,5-pentafluoropentyl) thio) butano-1-ol

BBr ₃ (1M in DCM, 2.9 mL, 2.9 mmol), and has been DCM (5 mL) solution of cooled to -78 ° C. (4-(benzyloxy) butyl) (4,4,5,5,5 -Pentafluoropentyl) sulfane (340 mg, 0.95 mmol) was added dropwise to the solution. The temperature was allowed to warm to room temperature and the mixture was stirred for 18 hours. Water was added slowly and the reaction mixture was stirred for 10 minutes. The two layers were separated and the aqueous layer was extracted with DCM (3x). The organics were combined, dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 50-100% EtOAc / hexane to give 171 mg of 4-((4,4,5,5,5-pentafluoropentyl as a colorless fatty oil ) Thio) Butano-1-ol was obtained.

(Intermediate 109)
4-((4,4,5,5,5-pentafluoropentyl) sulfinyl) butano-1-ol

  m-CPBA (64 mg, 0.37 mmol), 4-((4,4,5,5,5-pentafluoropentyl) thio) butan-1-ol (76 mg, 0.28 mmol) in DCM (3 mL) Was added to the cooled (0 ° C.) solution of and stirred at 0 ° C. for 30 minutes. The reaction mixture was warmed to room temperature and partitioned between a saturated solution of sodium bicarbonate and DCM. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-10% MeOH / DCM to give 52 mg of 4-((4,4,5,5,5-pentafluoropentyl) as a white solid Sulfinyl) butano-1-ol was obtained.

(Intermediate 110)
5-Amino-3- (difluoromethyl) picolinonitrile Step 1: (5-Bromo-2-chloropyridin-3-yl) methanol

Methyl 5-bromo-2 in a mixture of NaBH ₄ (5.8 g, 152.6 mmol, 4 eq) and anhydrous CaCl ₂ (16.9 g, 152.6 mmol) in dry DCM (100 mL) at 0 ° C. -Chloronicotinate (9.5 g, 38.15 mmol) was added slowly. The resulting mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture at 0 ° C. The organic layer is separated, dried over sodium sulfate and concentrated in vacuo to give 6.8 g of (5-bromo-2-chloropyridin-3-yl) methanol (crude), which is further purified Used in the next step without. LCM [M + H] ^< +> 223.1.

Step 2: 5-bromo-2-chloronicotinaldehyde

A solution of (5-bromo-2-chloropyridin-3-yl) methanol (6.8 g, 30.6 mmol) in DCM (200 mL) at 0 ° C. dez-Martin periodinane (32.4 g, 76.6 mmol) Added. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture is concentrated in vacuo and the residue is purified by column chromatography on silica gel (0-30% EtOAc in petroleum ether), 5.05 g of 5-bromo-2-chloronicotina I got Rudede. LCM [M + H] ⁺ 221.1.

Step 3: 5-bromo-2-chloro-3- (difluoromethyl) pyridine

A solution of 5-bromo-2-chloronicotinaldehyde (5.05 g, 23.2 mmol) in DCM (30 mL) at room temperature with ethanol (0.13 mL, 2.32 mmol) and DAST (7.51 g, 46. 4 mmol) were added. The resulting mixture was stirred at that temperature for 2 hours. To the reaction mixture was slowly added saturated aqueous sodium bicarbonate (100 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-50% EtOAc in petroleum ether) to give 3.80 g of 5-bromo-2-chloro-3- (difluoromethyl) pyridine. LCM [M + H] ^< +> 243.1.

Step 4: 5-amino-3- (difluoromethyl) picolinonitrile

  The title compound was synthesized as described in Intermediate 1 (Steps 3-5) using 5-bromo-2-chloro-3- (difluoromethyl) pyridine as the starting material.

<Example 1: Synthesis of Compound 1 (Thiohydantoin Synthesis Method A)>
5- (5- (3-Fluoro-4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolino Nitrile

  Thiophosgene (1.3 mL, 16.04 mmol), 5-amino-3- (trifluoromethyl) picolinonitrile (intermediate 1, 3 g, 16.0 mmol) and 1-((3-) in DMA (40 mL) To fluoro-4-hydroxyphenyl) amino) cyclobutane-carbonitrile (Intermediate 19, 3.3 g, 16.0 mmol), the mixture was heated to 60 ° C. for 18 hours. MeOH (60 mL) and HCl (2 M, 40 mL) were added and the mixture was refluxed for 2 hours. The mixture was cooled to room temperature and poured slowly into an ice / water bath. The brown solid is filtered, washed with water, dried and purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give 3 g of 5- (5- (5- (beige solid) as a beige solid 3-Fluoro-4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained.

<Example 2: Synthesis of Compound 2 (Thiohydantoin Synthesis Method B)>
5- (4-hydroxyphenyl) -6-thioxo-7- (3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) -5,7- Diazaspiro [3.4] octano-8-one

6-isothiocyanato-3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazine (Intermediate 8, 545 mg, 2.22 mmol) and 1-((DMA) in DMA (15 mL) A mixture of 4-hydroxyphenyl) amino) cyclobutanecarbonitrile (Intermediate 25, 418 mg, 2.22 mmol) was heated to 60 ° C. for 2 hours. MeOH (10 mL) and HCl (2 M, 10 mL) were added and the mixture was refluxed for 1 h. The mixture was cooled to room temperature and poured slowly into an ice / water bath. The dark brown solid is filtered, washed with water, dried and purified by reverse phase HPLC (acetonitrile / water: TFA) to give 5- (4-hydroxyphenyl) -6-thioxo-7 as a light brown solid -(3- (trifluoromethyl)-[1,2,4] triazolo [4,3-b] pyridazin-6-yl) -5,7-diazaspiro [3.4] octano-8-one was obtained . LCM [M + 1] ⁺ 435.4.

Example 3 Synthesis of Compound 3
Ethyl 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl)- 2-Fluorobenzoate

  Thiophosgene (0.55 mL, 5.35 mmol) in DMA (25 mL), 5-amino-3- (trifluoromethyl) picolinonitrile (Intermediate 1, 1 g, 5.35 mmol), and ethyl 4-((1 A mixture of -cyanocyclobutyl) amino) -2-fluorobenzoate (Intermediate 20, 1.4 g, 5.35 mmol) was heated to 70 ° C. overnight. MeOH (20 mL) and HCl (2 M, 20 mL) were added and the mixture was refluxed for 2 hours then cooled to room temperature. Water / ice was added and the aqueous layer was extracted with DCM (4x). The organics were combined, dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give 1 g of ethyl 4- (7- (6-cyano-5- (trifluoromethyl) pyridine as a yellow foam -3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluorobenzoate was obtained.

Example 4 Synthesis of Compound 4
5- (5- (4-Bromo-3-fluorophenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolino Nitrile

  Thiophosgene (0.36 mL, 4.67 mmol), 5-amino-3- (trifluoromethyl) picolinonitrile (Intermediate 1, 795 mg, 4.25 mmol) in DMA (30 mL) and 1-((4- To a solution of bromo-3-fluorophenyl) amino) cyclobutanecarbonitrile (Intermediate 90, 1.14 g, 4.25 mmol) was added dropwise. The resulting mixture was heated to 60 ° C. overnight. MeOH (8 mL) and HCl (2 M, 8 mL) were added and the mixture was refluxed for 2 hours then cooled to room temperature. Water was added slowly until a light brown solid precipitated. The solid was filtered, washed with water, dried, dissolved in MeOH and absorbed on silica gel. Purification by column chromatography on silica gel eluting with 10% EtOAc / hexane gave 616 mg of 5- (5- (4-bromo-3-fluorophenyl) -8-oxo-6-thioxo as a white solid. 5,7-Diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained.

Example 5 Synthesis of Compound 5
4- (7- (6-Cyano-5-methylpyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N -Methyl benzamide

  5-isothiocyanato-3-methylpicolinonitrile (intermediate 6, 2.9 g, 16.57 mmol) and 4-((1-cyanocyclobutyl) amino) -2-fluoro-N-methylbenzamide (intermediate in DMA) A mixture of 21, 2.7 g, 11.05 mmol) was heated to 65 ° C. overnight. MeOH (50 mL) and HCl (2 M, 70 mL) were added and the mixture was heated to 105 ° C. for 1 h then cooled to room temperature. Water was added slowly until a yellow solid precipitated and the mixture was stirred at room temperature for 3 hours. The solid was filtered, washed with water, dissolved in DCM, dried over sodium sulfate and absorbed onto silica gel. Purification by column chromatography on silica gel eluting with 0-100% EtOAc / hexanes gave a pale yellow solid. The solid is triturated with MeOH, filtered and dried to give 1.39 g (29%) of 4- (7- (6-cyano-5-methylpyridin-3-yl) -8- as a white solid. Oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N-methylbenzamide was obtained.

Example 6 Synthesis of Compound 6
4- (3- (6-Cyano-5-methylpyridin-3-yl) -4-oxo-2-thioxo-1,3-diazaspiro [4.4] nonan-1-yl) -2-fluoro-N -Methyl benzamide

Thiophosgene (0.35 mL), 4-((1-cyanocyclopentyl) amino) -2-fluoro-N-methylbenzamide (Intermediate 103, 400 mg, 1.53 mmol) in DMA (30 mL) under N ₂ atmosphere And 5-amino-3-methylpicolinonitrile (Intermediate 2, 303 mg, 2.28 mmol) were added dropwise. The resulting mixture was stirred at 60 ° C. overnight. MeOH (22 mL) and HCl (2 M, 11 mL) were added and the mixture was refluxed for 2 hours then cooled to room temperature. The reaction mixture was poured into water (75 mL) and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (1: 5 EtOAc / petroleum ether) and 300 mg of 4- (3- (6-cyano-5-methylpyridin-3-yl) as a pale yellow solid ) -4-Oxo-2-thioxo-1,3-diazaspiro [4.4] nonan-1-yl) -2-fluoro-N-methylbenzamide was obtained.

Example 7 Synthesis of Compound 7
3-Methyl-5- (5- (4- (5-methylfuran-2-yl) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) picory Noni

  Thiophosgene (0.1 mL), 1-((4- (5-methylfuran-2-yl) phenyl) amino) cyclobutanecarbonitrile (intermediate 106, 280 mg, 1.11 mmol) and 5 in DMA (20 mL) To a solution of -amino-3-methylpicolinonitrile (Intermediate 2, 177 mg, 1.33 mmol) was added dropwise. The resulting mixture was stirred at 60 ° C. overnight. MeOH (16 mL) and HCl (2 M, 8 mL) were added and the mixture was refluxed for 2 h and then cooled to room temperature. The reaction mixture was poured into water (200 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (1: 3 EtOAc / petroleum ether) and 140 mg 3-methyl-5- (5- (4- (5-methylfuran-2-yl) phenyl) ) 8-Oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) picolinonitrile was obtained.

  Compounds 8 to 117 were synthesized from the appropriate amine (either an amine was commercially available, either synthesized in the section of the intermediate or synthesized from literature procedures) and an amino cyanohydrin, according to the conditions indicated Yes (see footnote):

Example 8 Synthesis of Compound 118
5- (8-Oxo-5- (4- (piperazin-1-yl) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) Picolinonitrile

  Tert-Butyl 4- (4- (1-cyanocyclobutylamino) phenyl) piperazine-1-carboxylate (Intermediate 86, 0.25 g, 0.70 mmol) and 5-isothiocyanato-3- in DMA (5 mL) A mixture of (trifluoromethyl) picolinonitrile (Intermediate 10, 241 mg, 1.05 mmol) was heated to 80 ° C. for 12 hours. Then 2M HCl / MeOH = 1/1 (10 mL) was added and the resulting mixture was heated at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water (3 ×), dried over sodium sulfate and concentrated in vacuo. The residue is purified by Prep-HPLC (20% acetonitrile in water) and 75 mg of 5- (8-oxo-5- (4- (piperazin-1-yl) phenyl) -6-thioxo-5,7 -Diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile is obtained.

Example 9 Synthesis of Compound 119
tert-Butyl 4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano- 5-yl) phenyl) piperazine-1-carboxylate

5- (8-Oxo-5- (4- (piperazin-1-yl) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) in dry DCM (2 mL) 3- (trifluoromethyl) picolinonitrile (15 mg, 0.031 mmol) to a solution of, TEA (6 [mu] l, 0.062 mmol) and a _{(Boc) 2 O (10mg,} 0.046mmol) was added. The mixture was stirred at room temperature for 3 hours and then concentrated. The residue is purified by column chromatography on silica gel (0-20% EtOAc in petroleum ether) to give 10 mg of tert-butyl 4- (4- (7- (6-cyano-5- (trifluoro) Methyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) phenyl) piperazine-1 -carboxyler was obtained.

Example 10 Synthesis of Compound 120
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -N -Methyl benzene sulfonamide

4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro- [3.4] in acetonitrile (1 mL) A mixture of octano-5-yl) benzenesulfonamide (compound 81, 97 mg, 0.20 mmol), methyl tosylate (37 mg, 0.20 mmol), and Cs ₂ CO ₃ (65 mg, 0.20 mmol) in a shielded tube Heated at 50 ° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3 ×).
The organic layer is dried over magnesium sulfate and concentrated to give a residue purified by column chromatography on silica gel (hexane: DCM: acetone = 5: 9: 1) to give 30 mg of 4 as a white solid -(7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] -octano-5-yl) -N -Methylbenzenesulfonamide was obtained.

Example 11 Synthesis of Compound 121
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -N , N-Dimethylbenzenesulfonamide

  The title compound was obtained as a by-product from the procedure described in Example 10.

Example 12 Synthesis of Compound 122
Methyl 4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5- Yl) phenyl) butanolo

  5-isothiocyanato-3-trifluoromethylpyridine-2-carbonitrile (intermediate 10, 582 mg, 2.54 mmol) and 4- (4- (1-cyanocyclobutylamino) phenyl) butanoic acid in DMF (3 mL) A mixture of (Intermediate 80, 410 mg, 1.59 mmol) was stirred at room temperature overnight. To this mixture was added methanol (4 mL) and HCl (2 M, 2 mL) and the resulting mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into cold water and extracted with EtOAc (3 ×). The organic layer was dried over magnesium sulfate and concentrated to dryness. Column chromatography of the residue on silica gel (hexane: EtOAc = 4: 1) gives 256 mg of methyl 4- (4- (7- (6-cyano-5- (trifluoromethyl) -pyridine) as a white solid -3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) phenyl) butanoate is obtained.

Example 13 Synthesis of Compound 123
5- (5- (4-Fluoro-3-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolino Nitrile

Trimethylsilyl iodide (7.0 ml, 51.1 mmol) was added to 5- (5- (4-fluoro-3-methoxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [5 in acetonitrile (50 mL). 3.4] Octano-7-yl) -3- (trifluoromethyl) picolinonitrile (compound 32, 3 g, 5.1 mmol) was added to a solution and the mixture was refluxed for 24 hours. The mixture was cooled to room temperature, poured into water and extracted with EtOAc (3x). The organics were combined, washed with a saturated solution of NaHSO ₃ , dried over MgSO ₄ and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with EtOAc / hexane = 1/5 to give 1.1 g of 5- (5- (4-fluoro-3-hydroxyphenyl) -8-oxo-6 -Thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained.

Example 14 Synthesis of Compound 124
5- (5- (4- (3- (4-Methylpiperazin-1-yl) propyl) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (Trifluoromethyl) picolinonitrile

5- (5- (4- (3-hydroxypropyl) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- in DCM (2 mL) A solution of (trifluoromethyl) picolinonitrile (compound 86, 66 mg, 0.14 mmol) and methanesulfonyl chloride (0.033 mL, 0.42 mmol) was stirred at room temperature for 2 hours. The solution was washed with water (2 ×) and brine, dried over magnesium sulfate and concentrated to give 80 mg of the corresponding mesylate without purification. Mesylate (45 mg, 0.084 mmol), methyl piperazine (0.02 mL, 0.17 mmol) and triethylamine (0.04 mL, 0.25 mmol) in dichloromethane were stirred overnight at room temperature and then refluxed for 16 hours . the mixture was partitioned between water and DCM, the aqueous layer was further extracted with DCM (2x). the combined organics were washed with brine, dried (MgSO _4), and concentrated. silica gel chromatography (0 20 mg of 5- (4- (4- (3- (4-methylpiperazin-1-yl) propyl) phenyl) -8-oxo-6- as a beige solid by purification with ̃80% EtOAc / hexane). Thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitriol It was obtained.

Example 15 Synthesis of Compound 125
5- (5- (benzo [d] oxazol-6-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picory Nononitrile step 1: 5- (5- (4-amino-3-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (tri) Fluoromethyl) picolinonitrile

5-Amino-3- (trifluoromethyl) picolinonitrile (Intermediate 1, 110 mg, 0.59 mmol) in anhydrous DMA (3 mL), benzo [d] oxazol-6-amine (Intermediate 79, 125 mg, A mixture of 0.59 mmol) and thiophosgene (0.05 mL, 0.60 mmol) was stirred at 60 ° C. for 16 hours. Then methanol (3 mL) and 2M HCl (1.5 ml) were added and the mixture was heated at 90 ° C. for 2 hours. The reaction mixture is cooled, poured into ice / water (40 mL) and the resulting solid is filtered to afford 150 mg of 5- (5- (4-amino-3-hydroxyphenyl) -8-oxo as a brown powder. -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained. LCM [M + 1] ⁺ 434.0.

Step 2: 5- (5- (benzo [d] oxazol-6-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoro) Methyl) picolinonitrile

5- (5- (4-Amino-3-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3 in anhydrous DMF (1 ml) A mixture of-(trifluoromethyl) picolinonitrile (60 mg, 0.14 mmol) and triethyl orthoformate (0.050 mL, 0.28 mmol) was heated at 100 C for 1 h. The mixture was extracted with EtOAc (3 ×), diluted with water, the organics combined, washed with water (2 ×), brine, dried (MgSO ₄ ) and concentrated. Purification by column chromatography, eluting with 30% EtOAc / hexane, gave 23 mg of 5- (5- (benzo [d] oxazol-6-yl) -8-oxo-6-thioxo as a pale yellow solid. 5,7-Diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was provided.

Example 16 Synthesis of Compound 126
5- (5- (3-Fluoro-4- (2- (1-methyl-1H-pyrazol-5-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4 ] Octano-7-yl) -3- (trifluoromethyl) picolinonitrile

5- (5- (3-Fluoro-4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (THF) in THF (5 mL) Trifluoromethyl) picolinonitrile (compound 1, 100 mg, 0.23 mmol), 2- (1-Methyl-1H-pyrazol-5-yl) ethanol (43.5 mg, 0.34 mmol), triphenylphosphine (89 mg) , 0.34 mmol) and diisopropyl azodicarboxylate (0.07 mL, 0.34 mmol) were stirred at room temperature for 18 hours. The reaction mixture is absorbed on silica gel and purified by column chromatography on silica gel eluting with EtOAc / hexane to give impure desired product which is repurified by reverse phase HPLC (acetonitrile / water: TFA) The The fractions containing the desired compound were combined, the acetonitrile was removed in vacuo and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer is extracted with DCM (3 ×), the organics are combined, dried over sodium sulfate and evaporated to dryness, 29 mg of 5- (5- (3-fluoro-4- (2- (2- ()) as beige solid. 1-Methyl-1H-pyrazol-5-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picory Obtained a nitrile. LCM [M + 1] ⁺ 545.5.

Example 17 Synthesis of Compound 127
5- (5- (3-Fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl ) -3- (Trifluoromethyl) picolinonitrile

  5- (5- (3-Fluoro-4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (THF) in THF (5 mL) Trifluoromethyl) picolinonitrile (compound 1, 100 mg, 0.23 mmol), 2- (pyrrolidin-1-yl) ethanol (35 μL, 0.30 mmol), triphenyl phosphine (79 mg, 0.30 mmol), and diisopropyl A mixture of azodicarboxylate (60 μL, 0.30 mmol) was stirred at room temperature for 2 days. The reaction mixture is absorbed on silica gel and purified by column chromatography on silica gel eluting with 0-10% MeOH / DCM and repurified by reverse phase HPLC (acetonitrile / water, 0.1% TFA) The impure desired product obtained is obtained. The fractions containing the desired compound were combined, the acetonitrile was removed in vacuo and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer is extracted with DCM (3 ×), the organics are combined, dried over sodium sulfate and evaporated to dryness, 30 mg of 5- (5- (3-fluoro-4- (2-) as a white solid. (Pyrrolidin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained .

Example 18 Synthesis of Compound 128
5- (5- (4- (benzyloxy) -3-fluorophenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) ) Picolinonitrile

  5- (5- (3-Fluoro-4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (THF) in THF (5 mL) Trifluoromethyl) picolinonitrile (Example 1, 100 mg, 0.23 mmol), benzyl alcohol (35 μL, 0.30 mmol) triphenylphosphine (79 mg, 0.30 mmol), and diisopropyl azodicarboxylate (60 μL, 0) The mixture of .30 mmol) was stirred at room temperature for 2 days and then heated to 60 ° C. overnight. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with 0-50% EtOAc / hexane to give impure desired product. The solid is triturated in MeOH, filtered and dried to give 36 mg of 5- (5- (4- (benzyloxy) -3-fluorophenyl) -8-oxo-6-thioxo-5 as a white solid. 7,7-Diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained.

Example 19 Synthesis of Compound 129
5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3 -(Trifluoromethyl) picolinonitrile

  5- (5- (4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoro) in anhydrous THF (2 mL) Methyl) picolinonitrile (compound 63, 150 mg, 0.36 mmol), 1-methylpiperidin-ol (50 μL, 0.39 mmol), and a solution of triphenylphosphine (125 mg, 0.47 mmol) in diisopropylazodicarboxy The reaction (0.1 mL, 0.47 mmol) was added and the reaction mixture was stirred at room temperature overnight. Additional 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), triphenylphosphine (125 mg, 0.47 mmol) and diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) are added and the reaction is further Stir for 16 hours. The mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc (2x). The combined organics were washed with water and brine then dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0-80% EtOAc / hexanes then 0-5% MeOH / dichloromethane) is further purified by preparative HPLC (40-75% acetonitrile / water, 0.1% TFA) Impure product which is 45 mg of 5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5, as a pale yellow solid. 7-Diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained.

  Compounds 130-201 are described in Example 16 from the appropriate phenols and alcohols (phenols and alcohols were commercially available, synthesized in the Intermediates section, or synthesized from published procedures). Were synthesized according to the following procedure.

Example 20 Synthesis of Compound 202
5- (5- (4- (2- (4-acetylpiperazin-1-yl) ethoxy) -3-fluorophenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano- 7-yl) -3- (trifluoromethyl) picolinonitrile

  5- (5- (3-Fluoro-4- (2- (piperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4 in DCM (2 mL) A mixture of octano-7-yl) -3- (trifluoromethyl) picolinonitrile (compound 174, 50 mg, 0.1 mmol), acetic anhydride (13 μL, 0.14 mmol), and triethylamine (40 μL, 0.27 mmol) The solution was stirred at room temperature for 2 days. The reaction mixture is absorbed on silica gel and purified by column chromatography on silica gel eluting with 0-10% MeOH / DCM to give 34 mg of 5- (5- (4- (2- (2- (2-) as a white solid) 4-acetylpiperazin-1-yl) ethoxy) -3-fluorophenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) Picolinonitrile was obtained.

Example 21 Synthesis of Compound 203
5- (5- (3-Fluoro-4-methoxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolino Nitrile

5- (5- (3-Fluoro-4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (acetone) in acetone (4 mL) A mixture of trifluoromethyl) picolinonitrile (compound 1, 100 mg, 0.23 mmol), methyl iodide (0.14 mL, 0.23 mmol), and potassium carbonate (31 mg, 0.23 mmol) is stirred at room temperature for 4 hours did. The excess potassium carbonate is removed and the reaction mixture is absorbed on silica gel and purified by column chromatography on silica gel eluting with 0-30% EtOAc / hexane to give 74 mg of 5- (5-) as a white solid. (3-Fluoro-4-methoxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile was obtained. LCM [M + 1] ⁺ 451.4

  Compounds 204 and 205 were synthesized according to the procedure described in Example 21 from the appropriate phenol.

Example 22 Synthesis of Compound 206
5- (8-Oxo-5- (4- (pyrimidin-2-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) Picolinonitrile

5- (5- (4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (anhydrous THF (1.2 mL) A mixture of trifluoromethyl) picolinonitrile (compound 63, 50 mg, 0.12 mmol), 2-chloropyrimidine (17 mg, 0.15 mmol), and cesium carbonate (60 mg, 0.18 mmol) was heated at reflux overnight . The reaction mixture was cooled to room temperature and water was added. The aqueous layer was extracted with EtOAc (3 ×), the organics combined, washed with brine, dried (MgSO ₄ ) and concentrated. Purification by column chromatography on silica gel eluting with 0-60% EtOAc / hexanes gives 30 mg of 5- (8-oxo-5- (4- (pyrimidin-2-yloxy) phenyl) as an off-white solid -6- Thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile provided.

Example 23 Synthesis of Compound 207
5- (8-Oxo-5- (4- (pyrazin-2-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) Picolinonitrile

5- (5- (4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (an) in anhydrous DMF (1.4 mL) A mixture of trifluoromethyl) picolinonitrile (compound 63, 100 mg, 0.24 mmol), NaH (14 mg, 0.36 mmol, 60% dispersion in oil) and chloropyrazine (0.025 mL, 0.29 mmol) Heated at 90 ° C. for 16 hours. Additional chloropyrazine (0.025 mL, 0.29 mmol) was added and heating continued for 16 hours. The reaction mixture was cooled to room temperature and water was added. The aqueous layer was extracted with EtOAc (3 ×), the organics combined, washed with brine, dried (MgSO ₄ ) and concentrated. Purification by column chromatography on silica gel eluting with 0-50% EtOAc / hexane gave 50 mg of impure product. Further purification by preparative HPLC (30-100% acetonitrile / water, 10 minutes) gave 10 mg of 5- (8-oxo-5- (4- (pyrazin-2-yloxy) phenyl) -6 as an off-white solid -Thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile provided.

  Compounds 208 and 209 were synthesized from the appropriate phenol according to the procedure described in Example 23.

Example 24 Synthesis of Compound 210
3-Methyl-5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) picolinonitrile

  5- (5- (4-hydroxyphenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3-methylpicolinonitrile (according to Example 16 300 mg, 0.55 mmol of tert-butyl 4- (4- (7- (6-cyano-5-), prepared by reaction of compound 77) with tert-butyl 4-hydroxypiperidine-1-carboxylate Methyl pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) phenoxy) piperidine-1-carboxylate, 2M HCl overnight at room temperature Stir in / methanol (1 ml). The mixture is concentrated and purified by column chromatography, eluting with 10% MeOH / DCM, 230 mg of 3-methyl-5- (8-oxo-5- (4- (piperidine-4) as a white solid -Iroyloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) picolinonitrile is provided.

Example 25 Synthesis of Compound 211
5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (trifluoromethyl) Picolinonitrile

  The title compound was synthesized as described in Example 24 using compound 63 as the starting material.

Example 26 Synthesis of Compound 212
5- (8-Oxo-5- (4-((1-propionylpiperidin-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3 -(Trifluoromethyl) picolinonitrile

  Propionyl chloride (17 μL, 0.2 mmol) is added to 5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3 in THF (2 mL). .4] Octano-7-yl) -3- (trifluoromethyl) picolinonitrile is added to a mixture of 50 mg, 0.1 mmol) and triethylamine (28 μL, 0.2 mmol) and the resulting emulsified mixture is Stir at room temperature overnight. Methanol is added to quench the reaction, and the mixture is absorbed on silica gel and purified by column chromatography on silica gel eluting with 50-100% EtOAc / hexane to give 21 mg of 5 as a white solid. -(8-Oxo-5- (4-((1-propionylpiperidin-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3- (Trifluoromethyl) picolinonitrile was obtained.

  Compounds 213-219 were synthesized according to the procedure described in Example 26 from the appropriate piperidine and the appropriate acid chloride, chloroformate, alkyl bromide, or sulfonyl chloride.

Example 27 Synthesis of Compound 220
5- (5- (4-((1-isopropylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3 -(Trifluoromethyl) picolinonitrile

  5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) in anhydrous THF (1 ml) To a solution of -3- (trifluoromethyl) picolinonitrile (50 mg, 0.10 mmol) was added 2-bromopropane (20 μL, 0.20 mmol) followed by cesium carbonate (100 mg, 0.30 mmol) . The reaction mixture was heated to 70 ° C. overnight. DMF (1 ml) was added to improve solubility and the reaction was heated at 85 ° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was further extracted with EtOAc (2x) and the combined organics were washed with water and then with brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave 5 mg of 5- (5- (4-((1-isopropylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro as an off-white solid. [3.4] octano-7-yl) -3- (trifluoromethyl) picolinonitrile provided.

Example 28 Synthesis of Compound 221
Ethyl 2- (4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano -5-yl) phenoxy) piperidin-1-yl) acetate

The title compound is obtained by using 5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl)-as a starting material. Synthesized as described in Example 27 using 3- (trifluoromethyl) picolinonitrile and ethyl 2-bromoacetic acid. LCM [M + 1] ⁺ 588.1.

Example 29 Synthesis of Compound 222
4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl ) Phenoxy) piperidine-1-carboxamide

  5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3 in DCM (3 mL) A mixture of-(trifluoromethyl) picolinonitrile (70 mg, 0.14 mmol) and isocyanatotrimethylsilane (23 μL, 0.17 mmol) was stirred at room temperature overnight. Water was added and the mixture was vigorously stirred for 1 hour. The aqueous layer was extracted with DCM (3x) and the organics were combined, dried over sodium sulfate and evaporated to dryness. Column chromatography on silica gel (0-20% MeOH / DCM), 55 mg of 4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) as a white solid ) 8-Oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) phenoxy) piperidine-1-carboxamide was obtained.

Example 30 Synthesis of Compound 223
5- (5- (4- (2-hydroxyethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-7-yl) -3-methylpicolinonitrile

  Dihydrofuran-2,5-dione (604 mg, 6.87 mmol) in DMF (5 mL), 5- (5- (4-hydroxyphenyl) -8-oxo-6-thioxo-5 in DMF (10 mL) , 7-diazaspiro [3.4] octano-7-yl) -3-methylpicolinonitrile (500 mg, 1.37 mmol) and potassium carbonate (378 mg, 2.74 mmol) and the resulting mixture is added Heated to 85 ° C. overnight. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was further extracted with EtOAc (2x) and the combined organics were washed with water and then with brine. The organics were dried over sodium sulfate, filtered and concentrated. Column chromatography on silica gel (50-100% EtOAc / hexanes) gave 396 mg of 5- (5- (4- (2-hydroxyethoxy) phenyl) -8-oxo-6-thioxo as a white solid. 5,7-Diazaspiro [3.4] octano-7-yl) -3-methylpicolinonitrile was obtained.

Example 31 Synthesis of Compound 224
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2 -Fluorobenzoic acid

  Ethyl 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano in MeOH (10 mL) A mixture of -5-yl) -2-fluorobenzoate (compound 3, 1 g, 2.03 mmol) and NaOH (3 M, 10 mL) was stirred at room temperature for 18 hours. Aqueous HCl (2 M) is added to the reaction mixture until pH = 2, the aqueous layer is extracted with DCM (5x), the organics are combined, dried over sodium sulfate, evaporated to dryness, light yellow solid Mg of 4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5- as Yl) -2-fluorobenzoic acid was obtained.

  Compounds 225-228 were synthesized according to the procedure described in Example 31 from the corresponding esters.

Example 32 Synthesis of Compound 229
5- (7- (6-Carbamoyl-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2 -Fluorobenzoic acid

  The title compound was synthesized as a by-product in the synthesis of compound 226.

Example 33 Synthesis of Compound 230
4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl ) Phenyl) -N-methylbutanamide

  4- (4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4 in DCM (2 mL) Triethylamine (0.013 mL, 0.09 mmol) and 4-nitrophenyl chloroformate (15 mg, 0.07 mmol) in a solution of octano-5-yl) phenyl) butanoic acid (Compound 227, 85 mg, 0.17 mmol) Was added. The mixture was stirred at room temperature for 1 h and methylamine (0.3 mL in THF, 2 M) was added. After 30 minutes, the mixture was diluted with water and extracted with EtOAc (2.times.). The organic layer was dried over magnesium sulfate and concentrated. Column chromatography on silica gel (hexane: EtOAc = 1: 1) gave 35 mg (40%) of 4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridine) as a white solid. 3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) phenyl) -N-methylbutanamide was obtained.

Example 34 Synthesis of Compound 231
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2 -Fluorobenzamide

  4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl in DCM To a suspension of) -2-fluorobenzoic acid (compound 224, 500 mg, 1.08 mmol), DMF (cat., 0.1 mL) is added followed by the addition of oxalyl chloride (0.14 mL, 1.61 mmol) The The mixture was stirred at room temperature for 4 hours, concentrated in vacuo to yield a yellow residue which was further dried on high vacuum pump. Ammonia (0.5 M in dioxane, 40 mL, 20 mmol) was added directly to the residue and the mixture was stirred at room temperature overnight. MeOH is added, the mixture is absorbed on silica gel, purified by flash chromatography (50-100% EtOAc / hexane) and repurified by reverse phase HPLC (acetonitrile / water: TFA) impure desired product I got a thing. The fractions containing the desired compound were combined, the acetonitrile was removed in vacuo and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer is extracted with DCM (3 ×), the organics are combined, dried over sodium sulfate, evaporated to dryness and 100 mg of 4- (7- (6-cyano-5- (trifluoro) as a white solid. Methyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluorobenzamide was obtained.

  Compounds 232 and 233 were synthesized from the appropriate carboxylic acid according to the procedure described in Example 34.

Example 35 Synthesis of Compound 234
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2 -Fluoro-N- (2- (pyrrolidin-1-yl) ethyl) benzamide

4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3 in DCM (3 mL) and DMF (1 ml) .4] Octano-5-yl) -2-fluorobenzoic acid (compound 224, 100 mg, 0.21 mmol), 2- (pyrrolidin-1-yl) ethanamine (32 mg, 0.28 mmol), HATU (106 mg, 0. 1). A mixture of 28 mmol) and DIEA (0.1 mL, 0.63 mmol) was stirred at room temperature for 18 hours. Brine and EtOAc were added, the aqueous layer was extracted with EtOAc (4x), the organics were combined, dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-10% MeOH / DCM to give impure desired product repurified by reverse phase HPLC (acetonitrile / water: TFA) . The fractions containing the desired compound were combined, the acetonitrile was removed in vacuo and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer is extracted with DCM (3 ×), the organics are combined, dried over sodium sulfate, evaporated to dryness and 88 mg of 4- (7- (6-cyano-5- (tri) as an off white solid Fluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N- (2- (pyrrolidin-1-yl) ) Ethyl) benzamide was obtained. LCMS [M + 1] ⁺ 561.1.

Example 36 Synthesis of Compound 235
N-benzyl-4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5- Yl) -2-fluorobenzamide

4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano- in DMF (3 mL) 5-yl) -2-fluorobenzoic acid (compound 224, 68 mg, 0.14 mmol), benzylamine (22 mg, 0.21 mmol), HATU (70 mg, 0.18 mmol), and DIEA (40 μL, 0.21 mmol) The mixture was stirred at room temperature for 3 hours. The crude reaction mixture is purified by reverse phase HPLC (acetonitrile / water: TFA) to give 51 mg of N-benzyl-4- (7- (6-cyano-5- (trifluoromethyl) pyridine) as a white solid. 3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluorobenzamide was obtained.

Example 37 Synthesis of Compound 236
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2 -Fluoro-N- (2- (pyridin-2-yl) ethyl) benzamide

  4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano- in DMF (3 mL) 5-yl) -2-fluorobenzoic acid (compound 224, 70 mg, 0.15 mmol), 2- (pyridin-2-yl) ethanamine (24 mg, 0.20 mmol), HATU (74 mg, 0.20 mmol), and DIEA A mixture of (80 μL, 0.45 mmol) was stirred at room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile / water, 0.1% TFA). The fractions containing the desired compound were combined, the acetonitrile was removed in vacuo and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer is extracted with DCM (3 ×), the organics are combined, dried over sodium sulfate, evaporated to dryness and 51 mg of 4- (7- (6-cyano-5- (trifluoro) as a white solid. Methyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N- (2- (pyridin-2-yl) Ethyl) benzamide was obtained.

Example 38 Synthesis of Compound 237
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2 -Fluoro-N- (3- (pyrrolidin-1-yl) propyl) benzamide

  4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano- in DMF (25 mL) 5-yl) -2-fluorobenzoic acid (compound 224, 550 mg, 1.18 mmol), 3- (pyrrolidin-1-yl) propano-1-amine (303 mg, 2.37 mmol), HATU (673 mg, 1.77 mmol) ), And a mixture of DIEA (0.6 mL, 3.54 mmol) was stirred at room temperature overnight. Brine and EtOAc were added, the aqueous layer was extracted with EtOAc (4x), the organics were combined, dried over sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 0-20% MeOH / DCM to give 4- (7- (6-cyano-5- (trifluoromethyl) as a pale orange solid Pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N- (3- (pyrrolidin-1-yl) propyl) Benzamide was obtained.

  The trifluoroacetate salt was prepared according to the following procedure: 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo in DMF (3 mL) -5,7-Diazaspiro [3.4] octano-5-yl) -2-fluorobenzoic acid (compound 224, 70 mg, 0.15 mmol), 3- (pyrrolidin-1-yl) propano-1-amine (25 mg) A mixture of 0.20 mmol), HATU (74 mg, 0.20 mmol), and DIEA (80 μL, 0.45 mmol) was stirred at room temperature overnight. The crude reaction mixture is purified by reverse phase HPLC (acetonitrile / water, 0.1% TFA) to give 60 mg of 4- (7- (6-cyano-5- (trifluoromethyl) as a pale yellow solid Pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N- (3- (pyrrolidin-1-yl) propyl) The benzamide 2,2,2-trifluoroacetate salt is obtained.

  Compounds 238-311 were synthesized according to the procedure described in Example 35 from the appropriate acids and amines (either the amines were commercially available or were synthesized from literature procedures).

Example 39 Synthesis of Compound 312
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -6,8-dioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro -N-methylbenzamide

Synthesized as described for Example 1 using (5-amino-3- (trifluoromethyl) picolinonitrile (Intermediate 1) in MeOH (8 mL), and 4-((1 4-Cyanocyclobutyl) amino) -2-fluoro-N-methylbenzamide (intermediate 21) 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo -6-Thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N-methylbenzamide (90 mg, 0.19 mmol) and H ₂ O ₂ (30%, 0.72 mL) The mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with water, brine and dried over magnesium sulfate. The residue obtained is purified by reverse phase HPLC (acetonitrile / water: TFA) to give 10 mg of 4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl)-as a white solid. 6,8-Dioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluoro-N-methylbenzamide was obtained.

Example 40 Synthesis of Compound 313
4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -N -(3- (3,3-difluoropyrrolidin-1-yl) propyl) -2-fluorobenzamide Step 1: 3- (4- (7- (6-cyano-5- (trifluoromethyl) pyridine) -3- Yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluorobenzamido) propyl methanesulfonic acid

  4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano- in THF (5 mL) A mixture of 5-yl) -2-fluoro-N- (3-hydroxypropyl) benzamide (compound 306, 80 mg, 0.15 mmol) and triethylamine (22 μL, 0.16 mmol) was cooled to 0 ° C. Methanesulfonyl chloride (23 μL, 0.3 mmol) was added dropwise and the mixture was stirred at room temperature overnight. Brine and EtOAc are added, the aqueous layer is extracted with EtOAc (2x), the organics are combined, dried over sodium sulfate, evaporated to dryness and used crude 3- (4- (7- (7-) (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -2-fluorobenzamido) propyl Methanesulfonic acid was obtained.

Step 2: 4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl ) -N- (3- (3,3-Difluoropyrrolidin-1-yl) propyl) -2-fluorobenzamide

  3- (4- (7- (6-Cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4 in 3 mL of THF (2 mL) A mixture of octano-5-yl) -2-fluorobenzamido) propyl (methanesulfonic acid (45 mg, 0.075 mmol), 3, 3-difluoropyrrolidine hydrochloride (54 mg, 0.37 mmol), and triethylamine (0.14 mL) , 1.05 mmol) was heated overnight to 70 ° C. Brine and EtOAc were added to the cooled reaction mixture, the aqueous layer was extracted with EtOAc (2 ×), the organics were combined and dried over sodium sulfate The residue was purified by reverse phase HPLC (acetonitrile / water: TFA) to give 4.2 mg of 4- (7- (6-cyano). 5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octano-5-yl) -N- (3- (3,3-difluoro) Pyrrolidin-1-yl) propyl) -2-fluorobenzamide was obtained.

(Assay)
<Example 41-AR In Cell Western Assay>
LNCaP cells (8,000 / well) were plated in poly-d-lysine coated plates in RPMI medium containing 10% Charcoal Dextran Stripped Serum. After 24 hours, cells were treated with 30 μM to 0.0003 μM of the compound. Twenty hours after adding the compound, cells were fixed (for 20 ') for 20' (30% formaldehyde in PBS). Cells were blocked with PBS 0.1% Triton (each 50 μl / well, 3 ×, 5 ′ for 50 ′) and LiCor blocking buffer (50 μl / well 90 ′). The wells are then incubated overnight at 4 ° C. with rabbit IgG androgen receptor antibody (AR-N20, Santa Cruz antibody) diluted 1: 1000 in LiCor blocking buffer / 0.1% Tween-20. did. The wells are washed with 0.1% Tween-20 / PBS (50 μl / well, 5 'each) and then (90') 0.2% Tween-20 / 0.01% SDS / in the dark. Goat anti-rabbit IRDyeTM 800 CW (1: 1000) and DRAQ5 DNA dye (1: 10,000 for a 5 mM stock) diluted in LiCor blocking buffer were incubated. The cells were washed in 0.1% Tween-20 / PBS (50 μl / well, 5 'each). The wash buffer was removed and the plate read using LiCor Odyssey.

Example 42-AR Fluorescence Polarization Assay (Invitrogen)>
The compounds to be tested were diluted in AR Green Assay Buffer (final DMSO: 0.6%) to the desired concentration of 2 × final. Fluormone AL green and rat AR ligand binding domain were diluted in AR green assay buffer containing 2 mM DTT to the desired concentration of 2X final (Fluormone: 2 nM, AR LBD: 50 nM). AR LBD / Fluormone solution was added to all wells of a 384 well black plate (10 μl / well). Compounds were added to AR LBD / Fluormone solution (10 μl / well).
The plates were incubated for 4 hours in the dark. The fluorescence polarization of each well was measured using an excitation wavelength of 485 nm and an emission wavelength of 530 nm.

Example 43-Prostate cancer cell viability assay
LNCaP, LNCaPAR, PC3, and VCaP cells were adjusted to a concentration of 30,000 cells per mL in RPMI with 10% FBS and 20 mM HEPES. Sixteen microliters of cell suspension was added to each well of a 384-well plate and the cells were incubated overnight to allow the cells to attach. The following day, 7 point, serial semilog dilutions of each compound were added to cells in 16 μL at final concentrations ranging from 30 to 0.003 μM. After 5 days of compound exposure, 16 μL of CellTiter-GLo (Promega, Madison WI) was added to the cells and the relative light units (RLU) of each well were measured. CellTiter-Glo supplemented with 32 μL serum free of cells was used to obtain background values. Percent viability of each sample was measured as follows:

(RLU sample-RLU background / RLU untreated cells-RLU background) x 100 =% viability

Example 44 LNCaP-AR Luciferase Transcription Receptor Assay
LNCaP-AR-Luc was kept in RPMI 1640 supplemented with 10% FCS (Cancer Res 2006; 66: (21). November 1, 2006). Transcription assays were performed by seeding 100 μL of cells at a density of 25,000 cells / mL in 96-well cell culture plates in RPMI 1640 supplemented with 10% charcoal stripped serum and allowed to attach overnight . For AR agonist assays, compounds were serially diluted and RPMI 1640 supplemented with 50 μL of compound and charcoal stripped serum was added to the cells. For AR antagonist assays, compounds were serially diluted and RPMI and R1881 supplemented with 50 μL of compound and charcoal stripped serum were added to the cells. The final R1881 concentration used in the antagonist assay was 0.1 nM. After 40 hours of incubation, the medium is removed and the cells in 40 μL of lysis buffer (25 mM Tris phosphate, 2 mM CDTA, 10% glycerol, 0.5% Triton X-100, 2 mM DTT) It dissolved. 50 μl Luciferase buffer (20 mM Tricine, 0.1 mM EDTA, 1.07 mM (MgCo ₃ ) ₄ Mg (OH) ₂ .5 H ₂ O, 2.67 mM MgSO ₄ , 33.3 mM DTT, 270 μM Firefly luciferase activity was measured immediately after addition of coenzyme A, 470 μM luciferin, 530 μM ATP).

Example 45-AR-VP16 DNA Binding Assay
HepG2 cells were maintained in RPMI 1640 supplemented with 10% FCS. AR-VP16 DNA binding assay was performed by seeding 100 μL of cells at a density of 250,000 cells / mL into 96-well cell culture plates in RPMI 1640 supplemented with 10% charcoal stripped serum. I made it adhere in the evening. Cells were transiently transfected with Lipofectin (Life Technologies) according to the manufacturer's protocol. With 33.3 ng AR-VP16 pCDNA3 (expression vector), 66.7 ng 4X ARE-Luciferase (receptor vector), 16.7 ng CMV pRL (normalization vector) and 43.3 ng pCMX (filler DNA) Triple transfection was performed. The transfected cells were incubated overnight and then treated with ligand. For agonist assays, compounds were serially diluted and RPMI 1640 supplemented with 50 μL of compound and charcoal stripped serum was added to the cells. For antagonist assays, compounds were serially diluted and RPMI supplemented with 50 μL of compound, charcoal stripped serum and methyltrienolone (R1881) was added to the cells. The final R1881 concentration used in the antagonist assay was 0.1 nM. After 48 hours of incubation, the medium is removed and the cells in 40 μL of lysis buffer (25 mM Tris phosphate, 2 mM CDTA, 10% glycerol, 0.5% Triton X-100, 2 mM DTT) It dissolved. 40 μL Luciferase buffer (20 mM Tricine, 0.1 mM EDTA, 1.07 mM (MgCo ₃ ) ₄ Mg (OH) ₂ .5 H ₂ O, 2.67 mM MgSO ₄ , 33.3 mM DTT, 270 μM Firefly luciferase activity was measured immediately after addition of coenzyme A, 470 μM luciferin, 530 μM ATP). 40 μL coelenterazine buffer (1.1 M NaCl, 2.2 mM Na ₂ EDTA, 0.22 M KxPO ₄ (pH 5.1), 0.44 mg / mL BSA, 1.3 mM NaN ₃ , 1. Renilla luciferase was measured after addition of 43 μM coelenterazine, final pH adjusted to 5.0.

  Exemplary biological data for representative compounds disclosed herein are presented in the following table:

Example 46 Cl-gate gated Cl channel antagonist radioligand binding assay
Cerebral cortex membrane homogenate (120 μg of protein) in buffer containing 50 mM Na ₂ HPO ₄ / KH ₂ PO ₄ (pH 7.4) and 500 mM NaCl with or without the test compound at 3 nM Incubate with [ ³⁵ S] -TBPS for 120 minutes at 22 ° C. Nonspecific binding is measured in the presence of 20 μM picrotoxinin. Following incubation, samples are rapidly filtered under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and 96 sample cell harvesters (Unifilter, Packard) ) And rinse several times with ice-cold 50 mM Tris-HCl. The filters are dried and then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as percent inhibition of control radioligand specific binding. Standard reference compounds are Picrotoxinin, it, at several concentrations in each experiment, in order to obtain a competition curve in which the IC ₅₀ of the calculated and examined.

  In this assay, the following representative compounds disclosed herein showed less than 65% inhibition at 10 μM in a GABA gated Cl channel binding assay: Compound 5, Compound 13, Compound 124 Compound 168, Compound 171, Compound 208, Compound 218, Compound 37, Compound 268, Compound 291.

(In vivo assay)
Example 47: Castration resistant prostate cancer xenograft study
Six to seven week old male SCID hairless outbred mice (SHO, Charles Rivers Laboratories) were bilaterally orchiectomy under isoflurane anesthesia. LNCaP / AR cells were grown in RPMI at 37 ° C., 5% CO ₂ . Cells were centrifuged and resuspended in 50% serum free RPMI and 50% Matrigel at 1 × 10 ⁷ cells / ml. LNCaP / AR cells were injected subcutaneously (100 μl / animal) on the right flank after 3-5 days of castration. Every week, the tumor volume (length x width ^2/2) were monitored. Animals were randomized into treatment groups when tumors reached an average volume of ̃200 mm ³ . Tumor volume was monitored biweekly during the treatment period. At the end of the study, tumors were harvested and stored for further analysis.

(Pharmaceutical composition)
Example 48: Parenteral composition
Formulas (I), (Ia), (II), (III), (IV), (IV), (for the preparation of parenteral pharmaceutical compositions suitable for administration by injection (subcutaneous, intravenous, etc.) 100 mg of a water-soluble salt of a compound of V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (X) is dissolved in sterile water and then 0.9% Mixed with 10 mL of sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

  In another embodiment, an injectable formulation is formed by mixing the following ingredients: Formula (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) or (IX) 1.2 g of the compound of X), 2.0 mL of sodium acetate buffer (0.4 M), HCl (1 N) or NaOH (1 M) (qs to proper pH (qs)), water (distilled , Sterile) (qs to 20 mL). Combine all the above ingredients except water, stir and heat if necessary. Then add a sufficient amount of water.

Example 49 Oral Solution
To prepare a pharmaceutical composition for oral delivery, a water soluble 20% propylene glycol solution is prepared. To this, sufficient amounts of formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) ), (IXa) or (X) is added, and the compounds of formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII) A 20 mg / mL solution of the compound of (VIIIa), (IX), (IXa) or (X) is obtained.

Example 50: Oral capsule preparation
Formula (I), (Ia), (II), (III), (IV), (V), (V), (VI), (VII), (VIII) for preparing a pharmaceutical composition for oral delivery 100 mg of a compound of (VIIIa), (IX), (IXa) or (X), (X) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit such as a hard gelatine capsule, which is suitable for oral administration.

  In another embodiment, Formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX) 100 mg of the compound of (IXa) or (X) are placed in size 4 capsules or size 1 capsules (hypromellose or hard gelatine) and the capsules are closed.

Example 51 Oral Tablet
The tablets can be prepared according to the formulas (I), (Ia), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIIIa), (IX), (IXa) Or (X), prepared by mixing 48% by weight of crystalline cellulose, 45% by weight of crystalline cellulose, 5% by weight of low substituted hydroxypropyl cellulose, and 2% by weight of magnesium stearate. The tablets are prepared by direct compression. The total weight of the compressed tablet is kept at 250 mg.

<Example 52: Gel composition for topical use>
Formula (I), (Ia), (II), (III), (IV), (V), (V), (VI), (VII), (VIII) for preparing a pharmaceutical gel composition for topical use 100 mg of a compound of (VIIIa), (IX), (IXa) or (X) are mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then placed in a container (such as a tube) suitable for topical administration.

  The examples and embodiments described herein are for illustrative purposes only, and various modifications or alterations suggested to one skilled in the art should be made within the spirit and scope of the present application, as well as the appended claims. Should be included in the scope.

Claims (38)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient, and a compound of formula (VIIIa), or a pharmaceutically acceptable salt thereof, wherein said composition is a single dose Formulated in a dosage form suitable for delivering a therapeutically effective amount of said compound when administered in the form or when administered multiple times over a period of 1 day,
During the ceremony
Both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl.
Or
Each R ¹ is independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ fluoroalkyl,
X is O or S,
R ^A is C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl,
Ring B is phenyl,
n is 0, 1 or 2;
R ⁴ is a halogen, —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy or C ₁ -C ₆ heteroalkyl, wherein heteroalkyl is one or more skeletal atoms of alkyl , An alkyl group substituted by atoms of, oxygen, nitrogen, sulfur, or combinations thereof,
R ⁵ is L ¹ -L ² -R ⁶ or L ¹ -R ⁷ ,
L ¹ is —O—, —S—, —OC (= O) —, or —OC (= O) O—
L ² is C ₁ -C ₆ alkylene, and R ⁶ or R ⁷ is optionally substituted piperidinyl, optionally substituted morpholinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or thiomorpholinyl Yes,
The optional substituents are C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -CN, halo, -C (O) -O- (C ₁ -C ₆ alkyl), -CH ₂ -C (O) -O- _(C 1 -C _{6 alkyl), - NH 2, -NH (} C 1 -C 6 _{alkyl), - N (C 1 -C} 6 _{alkyl) 2, -OH, -CO 2 H} , -C ( _{O) NH 2, -C (O} ) NH (C 1 -C 6 _{alkyl), - C (O) N} (C 1 -C 6 _{alkyl) 2,} C 1 -C _{6 alkoxy,} C 1 -C ₆ fluoroalkoxy , -Sulfonyl (C ₁ -C ₆ alkyl),-(C ₁ -C ₆ alkylene) -OH, and -C (O)-(C ₁ -C ₆ alkyl), selected from
Each R ⁹ is independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl, and each R ¹⁰ is independently characterized by C ₁ -C ₆ alkyl. Pharmaceutical composition. X is S,
Both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl.
Or
Each R ¹ is independently C ₁ -C ₆ alkyl,
R ⁴ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy;
L ¹ is —O—, and R ⁶ or R ⁷ is optionally substituted piperidinyl, and the optional substituent is alkyl, —C (O) —O— (C ₁ -C ₆ alkyl), -CH ₂ -C (O) -O- (C ₁ -C ₆ alkyl), -C (O) NH ₂ ,-(C ₁ -C ₆ alkyl) sulfonyl,-(C ₁ -C ₆ alkylene) -OH , -C (O) - _(C 1 -C ₆ alkyl), morpholinyl, at least one _C 1 -C _{6 alkyl,} C 1 -C ₆ fluoroalkyl, -C (O) - _(C 1 -C ₆ alkyl) Or piperazinyl optionally substituted with -C (O) -O- (C ₁ -C ₆ alkyl), pyrrolidinyl optionally substituted with at least one halo, tetrahydropyranyl, tetrahydrothiopyranyl, or thiomorpholinyl From the group Characterized in that it is-option, a pharmaceutical composition according to claim 1. R ^A is -CH ₃ , -CF ₃ or -OCH ₃ ,
Both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or each R ¹ is —CH ₃ ,
Characterized in that R ⁵ is ^L 1 -R ^7, A pharmaceutical composition according to claim 2. Said compound of formula (VIIIa) is
The pharmaceutical composition according to claim 3, having the structure of R ⁴ is fluoro,
Each R ⁹ is independently H or C ₁ -C ₆ alkyl,
R ¹⁰ is characterized in that it is a C ₁ -C ₆ alkyl, independently, a pharmaceutical composition according to any one of claims 1 to 4. R ^A is —CH ₃ or —CF ₃ ,
Both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or each R ¹ is —CH ₃ ,
The pharmaceutical composition according to claim 1, characterized in that n is 0 or 1 and R ⁴ is fluoro. The pharmaceutical composition according to claim 1, characterized in that R ⁶ or R ⁷ is optionally substituted piperidinyl. The pharmaceutical composition according to claim 1, characterized in that R ⁶ or R ⁷ is morpholinyl. R ⁶ or R ⁷ is at least one C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -C (O)-(C ₁ -C ₆ alkyl), or -C (O) -O- ( Pharmaceutical composition according to claim 1, characterized in that it is piperazinyl optionally substituted with C ₁ -C ₆ alkyl). The pharmaceutical composition according to claim 1, characterized in that R ⁶ or R ⁷ is pyrrolidinyl optionally substituted with at least one halo, tetrahydropyranyl, tetrahydrothiopyranyl or thiomorpholinyl. Said compound of formula (VIIIa) is
3-Methyl-5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Il) picolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3-methylpicolinonitrile,
5- (4,4-Dimethyl 3- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -5-oxo-2-thioxoimidazolidin-1-yl) -3-methylpicolino Nitrile,
3-Methyl-5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) picolinonitrile,
5- (5- (4-((1-acetylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -Methylpicolinonitrile,
5- (5- (4-((1-ethylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -Methylpicolinonitrile,
5- (5- (4-((1- (2-Hydroxyethyl) piperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7 -Yl) -3-methylpicolinonitrile,
5- (5- (4-((1- (2-Hydroxyethyl) piperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7 -Yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (trifluoromethyl) Picolinonitrile,
5- (8-Oxo-5- (4-((1-propionylpiperidin-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
5- (5- (4-((1-Isobutyrylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl) -3- (trifluoromethyl) picolinonitrile,
Ethyl 4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-5- (I) phenoxy) piperidine-1-carboxylate,
5- (5- (4-((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
5- (5- (4-((1-isopropylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
Ethyl 2- (4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane -5-yl) phenoxy) piperidin-1-yl) acetate,
4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-5-yl The pharmaceutical composition according to claim 1, which is phenoxy) piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof. Said compound of formula (VIIIa) is
5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
3-Methyl-5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Il) picolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3-methylpicolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
3-Methyl-5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) picolinonitrile,
5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (trifluoromethyl) The pharmaceutical composition according to claim 1, which is picolinonitrile, or a pharmaceutically acceptable salt thereof. Said compound of formula (VIIIa) is
5- (5- (3-Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3-methylpicolinonitrile,
5- (5- (3-Fluoro-4- (2- (piperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
5- (5- (4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
3-Methyl-5- (8-oxo-6-thioxo-5- (4- (2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethoxy) phenyl) -5, 7-Diazaspiro [3.4] octan-7-yl) picolinonitrile,
3-Methyl-5- (5- (4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) picolinonitrile,
5- (5- (4- (2- (4-acetylpiperazin-1-yl) ethoxy) -3-fluorophenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- The pharmaceutical composition according to claim 1, which is 7-yl) -3- (trifluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt thereof. Said compound of formula (VIIIa) is
5- (5- (3-Fluoro-4- (2-morpholinoethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (tri) Fluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (3-morpholinopropoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl) -3- (tri) Fluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (2-morpholinoethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (tri) Fluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (3-morpholinopropoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl) -3- (tri) The pharmaceutical composition according to claim 1, which is fluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt thereof. Said compound of formula (VIIIa) is
5- (5- (3-Fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
3-Methyl-5- (8-oxo-5- (4-((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octane-7 -Yl) picolinonitrile,
5- (8-Oxo-5- (4-((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl)- The pharmaceutical composition according to claim 1, which is 3- (trifluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt thereof. Use of a compound of formula (VIIIa) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an androgen receptor dependent or androgen receptor mediated disease or disorder in a mammal,
During the ceremony
Both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl.
Or
Each R ¹ is independently H, -OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ fluoroalkyl,
X is O or S,
R ^A is C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl,
Ring B is phenyl,
n is 0, 1 or 2;
R ⁴ is a halogen, —CN, —NO ₂ , —OH, —OR ⁹ , —SR ⁹ , —S (= O) R ¹⁰ , —S (= O) ₂ R ¹⁰ , C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy, C ₁ -C ₆ alkoxy or C ₁ -C ₆ heteroalkyl;
R ⁵ is L ¹ -L ² -R ⁶ or L ¹ -R ⁷ ,
L ¹ is —O—, —S—, —OC (= O) —, or —OC (= O) O—
L ² is C ₁ -C ₆ alkylene, and R ⁶ or R ⁷ is optionally substituted piperidinyl, optionally substituted morpholinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or thiomorpholinyl Yes,
The optional substituents are C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -CN, halo, -C (O) -O- (C ₁ -C ₆ alkyl), -CH ₂ -C (O) -O- _(C 1 -C _{6 alkyl), - NH 2, -NH (} C 1 -C 6 _{alkyl), - N (C 1 -C} 6 _{alkyl) 2, -OH, -CO 2 H} , -C ( _{O) NH 2, -C (O} ) NH (C 1 -C 6 _{alkyl), - C (O) N} (C 1 -C 6 _{alkyl) 2,} C 1 -C _{6 alkoxy,} C 1 -C ₆ fluoroalkoxy , -Sulfonyl (C ₁ -C ₆ alkyl),-(C ₁ -C ₆ alkylene) -OH, and -C (O)-(C ₁ -C ₆ alkyl), selected from
Each R ⁹ is independently H, C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl, and each R ¹⁰ is independently characterized by C ₁ -C ₆ alkyl. Use to do. X is S,
Both R ¹ are taken together with the carbon atom to which they are attached to form a C ₃ -C ₆ cycloalkyl.
Or
Each R ¹ is independently C ₁ -C ₆ alkyl,
R ⁴ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₁ -C ₆ fluoroalkoxy or C ₁ -C ₆ alkoxy;
L ¹ is —O—, and R ⁶ or R ⁷ is optionally substituted piperidinyl, and the optional substituent is alkyl, —C (O) —O— (C ₁ -C ₆ alkyl), -CH ₂ -C (O) -O- (C ₁ -C ₆ alkyl), -C (O) NH ₂ ,-(C ₁ -C ₆ alkyl) sulfonyl,-(C ₁ -C ₆ alkylene) -OH , -C (O) - _(C 1 -C ₆ alkyl), morpholinyl, at least one _C 1 -C _{6 alkyl,} C 1 -C ₆ fluoroalkyl, -C (O) - _(C 1 -C ₆ alkyl) Or piperazinyl optionally substituted with -C (O) -O- (C ₁ -C ₆ alkyl), pyrrolidinyl optionally substituted with at least one halo, tetrahydropyranyl, tetrahydrothiopyranyl, or thiomorpholinyl From the group Characterized in that it is-option, Use according to claim 16. R ^A is -CH ₃ , -CF ₃ or -OCH ₃ ,
Both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or each R ¹ is —CH ₃ and R ⁵ is L characterized in that it is a ¹ -R ^7, use according to claim 17. Said compound of formula (VIIIa) is
The use according to claim 18, characterized in that it has the following structure: R ⁴ is hydrogen or fluoro,
Each R ⁹ is independently H or C ₁ -C ₆ alkyl,
R ¹⁰ is characterized in that it is a _C 1 -C ₆ alkyl independently Use according to any one of claims 16 to 19. R ^A is —CH ₃ or —CF ₃ ,
Both R ¹ are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or each R ¹ is —CH ₃ ,
17. The use according to claim 16, characterized in that n is 0 or 1 and R ⁴ is fluoro. The use according to claim 16, characterized in that R ⁶ or R ⁷ is morpholinyl. R ⁶ or R ⁷ is at least one C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -C (O)-(C ₁ -C ₆ alkyl), or -C (O) -O- ( The use according to claim 16, characterized in that it is piperazinyl optionally substituted with C ₁ -C ₆ alkyl). R ⁶ or R ⁷ is characterized by at least one halo, tetrahydropyranyl, tetrahydrothiopyranyl pyrrolidinyl or optionally substituted thiomorpholinyl, Use according to claim 16. Said compound of formula (VIIIa) is
5- (5- (3-Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3-methylpicolinonitrile,
5- (5- (3-Fluoro-4- (2- (piperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
5- (5- (4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) -3- (trifluoromethyl) picolinonitrile,
3-Methyl-5- (8-oxo-6-thioxo-5- (4- (2- (4- (2,2,2-trifluoroethyl) piperazin-1-yl) ethoxy) phenyl) -5, 7-Diazaspiro [3.4] octan-7-yl) picolinonitrile,
3-Methyl-5- (5- (4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- 7-yl) picolinonitrile,
5- (5- (4- (2- (4-acetylpiperazin-1-yl) ethoxy) -3-fluorophenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane- The use according to claim 16, characterized in that it is 7-yl) -3- (trifluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt thereof. Said compound of formula (VIIIa) is
5- (5- (3-Fluoro-4- (2-morpholinoethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (tri) Fluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (3-morpholinopropoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl) -3- (tri) Fluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (2-morpholinoethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (tri) Fluoromethyl) picolinonitrile,
5- (5- (4-Fluoro-3- (3-morpholinopropoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl) -3- (tri) 17. The use according to claim 16, characterized in that it is fluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt thereof. Said compound of formula (VIIIa) is
5- (5- (3-Fluoro-4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4- (3- (pyrrolidin-1-yl) propoxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
3-Methyl-5- (8-oxo-5- (4-((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octane-7 -Yl) picolinonitrile,
5- (8-Oxo-5- (4-((tetrahydro-2H-pyran-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl)- The use according to claim 16, characterized in that it is 3- (trifluoromethyl) picolinonitrile, or a pharmaceutically acceptable salt thereof.   28. The use according to any one of claims 16 to 27, characterized in that the androgen receptor dependent or androgen receptor mediated disease or disorder is prostate cancer, breast cancer or uterine cancer.   The use according to claim 28, characterized in that the cancer is a hormone dependent cancer.   30. The use according to claim 29, wherein said hormone dependent cancer is prostate cancer.   31. The use according to any one of claims 16 to 30, characterized in that the formulation is for use in combination with at least one pharmaceutically active agent. Use of a compound, or a pharmaceutically acceptable salt thereof, in the manufacture of a formulation for treating an androgen receptor dependent or androgen receptor mediated disease or disorder in a mammal, said formulation comprising at least one of For use in combination with one pharmaceutically active agent, said compound
3-Methyl-5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Il) picolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3-methylpicolinonitrile,
5- (4,4-Dimethyl-3- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -5-oxo-2-thioxoimidazolidin-1-yl) -3-methylpicory Nonitrile,
3-Methyl-5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) picolinonitrile,
5- (5- (4-((1-acetylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -Methylpicolinonitrile,
5- (5- (4-((1-ethylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -Methylpicolinonitrile,
5- (5- (4-((1- (2-Hydroxyethyl) piperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7 -Yl) -3-methylpicolinonitrile,
5- (5- (4-((1- (2-Hydroxyethyl) piperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7 -Yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (trifluoromethyl) Picolinonitrile,
5- (8-Oxo-5- (4-((1-propionylpiperidin-4-yl) oxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
5- (5- (4-((1-Isobutyrylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7-yl) -3- (trifluoromethyl) picolinonitrile,
Ethyl 4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-5- (I) phenoxy) piperidine-1-carboxylate,
5- (5- (4-((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl ) -3- (Trifluoromethyl) picolinonitrile,
5- (5- (4-((1-isopropylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
Ethyl 2- (4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane -5-yl) phenoxy) piperidin-1-yl) acetate,
4- (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-5-yl ) Phenoxy) piperidine-1-carboxamide, or a pharmaceutically acceptable salt thereof. The compound is
5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3 -(Trifluoromethyl) picolinonitrile,
5- (5- (2-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
3-Methyl-5- (5- (4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Il) picolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3-methylpicolinonitrile,
5- (5- (3-Fluoro-4-((1-methylpiperidin-4-yl) oxy) phenyl) -8-oxo-6-thioxo-5,7-diazaspiro [3.4] octane-7- Yl) -3- (trifluoromethyl) picolinonitrile,
3-Methyl-5- (8-oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) picolinonitrile,
5- (8-Oxo-5- (4- (piperidin-4-yloxy) phenyl) -6-thioxo-5,7-diazaspiro [3.4] octan-7-yl) -3- (trifluoromethyl) The use according to claim 32, characterized in that it is picolinonitrile, or a pharmaceutically acceptable salt thereof.   The at least one pharmaceutically active agent is gossypol, genasense, polyphenol E, chlorofucin, all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor related apoptosis inducing ligand (TRAIL), 5-aza-2'- Deoxycytidine all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib, geldanamycin, 17-N-allylamino-17-demethokigeldanamycin (17-AAG), flavopyridol, LY 294002, bortezomib, trastuzumab, 34. A method according to any one of claims 31 to 33, characterized in that it comprises BAY 11-7082, PKC412 or PD184352, paclitaxel, or an analogue of paclitaxel. Use of the mounting.   The at least one pharmaceutically active agent is abiraterone, adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperin; Azetata; Azitamatite; Batimastat; Nomycin; carsterone; carassemide; carvetimer; carboplatin Carmustine hydrochloride; carselcin hydrochloride; carselcin; sedefingol; chlorambucil; chloremycin; cladribine; Doxorubicin; droloxifene; droloxifene citrate; dolomostanol propionate; duazamycin; Sodium acid; etanidazole; etoposide; phosphate etoposide; Topologically, fadrozole hydrochloride, pharazabin, fenretinide, phloxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, foschidone, fostrydon sodium, gemcitabine hydrochloride, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, imimophosin, interleukin Il Interferon α-2a; Interferon α-2b; Interferon α-n1; Interferon α-n3; Interferon β-la; Interferon γ-lb; Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Retro Leuprolide acetate; liarozole hydrochloride; lometelexole sodium; lomustine; rosoxantrone hydrochloride; Soprocall, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan acetate, menphagaril, mercaptopurine, methotrexate, methotrexate sodium, methoprine, metthuredepa; Mitophenol, Mycophenolic acid, Nocodazole, Nogalamycin, Ormaplatin, Oxislane, Pegaspulase, Periomycin, Pentamustine, Pepromycin Sulfate, Perphosphamide, Pipobroman, Piposulfan Hydrochloride, Piroxantrone Hydrochloride, Plicamycin, Promestane, Porphymer Sodium Porphyromycin; Prednimustine; Procarbazine hydrochloride; Puromycin hydrochloride; pyrazofurin; ribopurine; logretimide; safingol; safingol hydrochloride; semustine; shimtrazen; sparphosate sodium; sparsolomycin; spirogermanium hydrochloride; Thalisomycin sodium; tegafur; telxanthol hydrochloride; temoporphin; teniposide; teloxirone; test lactone; Trimetrexate; Triptorelin; Tubrosol Hydrochloride; Uracil Mustard; Uredepa; Vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; binglysinate sulfate; vin leulosin sulfate; vinorelbine tartrate; 34. Use according to any one of claims 31 to 33.   The at least one pharmaceutically active agent is dolastatin 10, mibobline isethionate, vincristine, NSC-639829, discodermolide, ABT-751, altriltin (such as altriltin A and altriltin C), spongystatin (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, Spongistatin 9, etc., Hydrochloride Semadotin, Epothilone (Epothilone A, Epothilone B, Epothilone C, Epothilone D, Epothilone E, Epothilone F, Epothilone B N-Oxide, Epothilone A N-Oxide, 16-Aza-Epothilone B, 21-Amino Epothilone B, 21-Hydroxy Epothilone D, 26-fluoroepothilone), auristatin PE, sobridotine, vincristine sulfate, cryptophysin 52, vitilevamide, tubulysin A, canadiansole, centauredin, oncocidin A1 fidianolide B, lauramarido, narcosine, nascapine, hemiasterin, bana Dense acetylacetonate, indanosine eleothelobin (desmethyl eleothelobin, desacetyl eleuterobin, isoerotelobin A, and Z-eloterobin etc.), caribeoside, cariberoin, halichondrin B, diazonamide A, Taccaronolide A, 34. The method according to any one of claims 31 to 33, characterized in that it comprises dizostatin, (-)-phenyl ahistin, myocevelin B, resverastatin sodium phosphate. Use as claimed in any one.   The at least one pharmaceutically active agent may be an antibiotic, an anti-estrogen agent, an anti-androgen agent, a gonadotropin releasing hormone analogue, a thrombolytic agent, an antiemetic agent, an agent useful for treating anemia, neutropenia 32. The method of claim 31, wherein the agent is useful for the treatment of corticosteroid, analgesic, kinase inhibitor, HSP90 inhibitor, histone deacetylase (HDAC) inhibitor, or non-steroidal anti-inflammatory drug. The use according to any one of 33 to 33.   16. A pharmaceutical composition according to any one of the preceding claims, formulated in an oral dosage form, comprising an amount ranging from 1 mg to 500 mg of said compound or a pharmaceutically acceptable salt thereof.